人口遺傳學導論(2010年) (Introduction to Population Genetics (2010))

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GOOD MORNING, EVERYONE. GREETINGS OF THOSE JOINING US THREW THE LIVE
FEED. THIS IS WEEK SEVEN OF THE COURSE IT'S MY PLEASURE
TO INTRODUCE TO YOU DR. LYNN JORDE FROM THE UTAH SCHOOL OF MEDICINE.
HER RESEARCH INTERESTS ARE IN THE AREA OF GENE MAP AND EVOLUTIONARY GENETIC.
HIS GROUP IS ANALYZING VARIATIONS IN GENE IN THE PATHWAY WITH THE GOAL OF HOPING TO
BETTER UNDERSTAND THE ROLE OF THESE GENES IN TO HYPERTENSION AND HIS WORK ALSO FOCUSES
ON A NUMBER OF OTHER DISORDERS SUCH AS THE GENETICS OF JUVENILE IDIOPATHIC ARTHRITIS
AND INFLAMMATORY BOWEL DISEASE. NUCLEAR DNA FOCUSING ON MOBILE ELEMENTS, THE
GOAL OF THIS WORK IS TO UNDERSTAND BETTER THE GEOGRAPHICAL ORIGIN AND MIGRATION OF MAN
AND HOW THESE DATA MIGHT BE USED TO DETERMINE THE RELEVANCE OF RACE, RACE IN QUOTATION MARKS
IN BIOMEDICAL SETTINGS WHICH THE DOCTOR WILL TALK TO YOU ABOUT THIS MORNING.
FINALLY, LYNN IS ONE OF THE MOST WONDERFUL LECTURERS THAT I KNOW I WAS VERY SURE THAT
YOU'RE GOING TO ENJOY TODAY AS LECTURE AND LEARN A LOT FROM HIM THIS MORNING.
TODAY'S LECTURE AGAIN IS INTENDED TO PROVIDE YOU AN OVERVIEW OF THE FIELD OF POPULATION
GENETICS MY PLEASURE TO INTRODUCE TO YOU. [APPLAUSE]
>> THANK YOU VERY MUCH. IT'S A PLEASURE TO BE BACK HERE AGAIN.
THIS MORNING I WOULD LIKE TO INTRODUCE YOU TO THE TWO OF THE FIELD OF POPULATION GENETICS.
MY TALK WILL BE DIVIDED IN THREE PARTS, AT THAT TIME EARNS -- PATTERNS OF HUMAN GENETICS
BOTH AMONG HUMAN AND AMONG INDIVIDUALS WHICH WE CAN NOW LOOK AT WITH SOME PRECISION.
WE'LL TALK ABOUT THE IMPLICATIONS OF THIS WORK FOR CONCEPTS OF RACE, SOMETHING THAT
IS CONTROVERSIAL AND SOMETHING THAT I THINK IS ILLUMINATED BY OUR GENETIC STUDIES.
THEN FINALLY IN THE THIRD PART OF THE TALK WE'LL DISCUSS HOW POPULATION GENETICS, EVOLUTIONARY
GENETICS INFORMS OUR UNDERSTANDING OF THINGS LIKE LINKAGE TO DISEQUILIBRIUM, THE HAPMAP
AND OUR CONTINUING SEARCH FOR GENES UPPED LYING DISEASE.
WITH MUTATION. THE GENERATOR OF GENETIC VARIATION.
WE ESTIMATE BASED ON PHYLOGENETIC ANALYSIS THAT THE HUMAN MUTATION RATE IS ABOUT 2.5
TIMES TO THE -- PER BASE PER PER GENERATION. WHAT THAT MEANS IS THAT WE TRANSMIT ABOUT
75 OR SO NEW DNA VARIANTS WITH EACH GAMETE. I SHOULD SAY THAT SOME OF THE NEW GENOME ANALYSES
OF FAMILIES ARE SUGGESTING THAT THIS RATE IS OVERESTIMATED AND THAT THE ACTUAL MUTATION
RATE MAY BE ABOUT HALF OF THIS. INTERESTING TO SEE AS THOSE STUDIES COME OUT
WHERE THE MUTATION RATE FINALLY LANDS. BUT WE THINK NOW IT MIGHT BE ROUGHLY HALF
OF THE USUALLY CITED PHYLOGENETIC ESTIMATE. HERE IS A QUOTE FROM LOUIS THAT I LIKE VERY
MUCH. HE SAID THE CAPACITY TO BLUNDER SLIGHTLY IS
THE REAL MARVEL OF DNA, WITHOUT THIS SPECIAL ATTRIBUTE WE WOULD STILL BE ANAEROBIC BACTERIA
AND BE NO NUCLEUS US. THAT IS A LOVELY QUOTE.
REMAINS US OF WHY WE SHOULD BE THANKFUL FOR OUR MUTATIONS.
WELL, ONE OF THE QUESTIONS THAT WE CAN ASK AS WE LOOK AT DNA VARIATION IN INDIVIDUALS
AND POPULATIONS SPECIE IS HOW MUCH AT THE DNA LEVEL DID WE DIFFER?
IF WE LOOK AT ALIGNED DNA BASE DIFFERENCES, IDENTICAL TWINS BEING NATURE'S CLONES HAVE
ZERO DNA SEQUENCE DIFFERENCES. A FAMOUS FIGURE NOW, IS THAT IF WE LOOK AT
ANY TWO UNRELATED HUMANS, FOR ALIGNED DNA BASE DIFFERENCES WE VARY ABOUT ONLY ONE IN
1,000. SEVERAL TIMES MORE THAN THIS IF YOU INCLUDE
COPY NUMBER VARIANTS BUT FOR ALIGNABLE SEQUENCE WE ARE AS HAS BEEN SAID MANY TIMES NOW 99.9%.
IF WE COMPARE OURSELVES IN THE SAME WAY TOURER NEAREST NEIGHBOR, THE CHIMP WE DIFFER ABOUT
1 IN A HUNDRED BASE PAIRS FROM THE CHIMP. IN THE SENSE WE'RE 99% CHIMP.
IF WE COMPARE OURSELVES TO MOUSE, ABOUT ONE IN THREE BASE DIFFERS COMPARES HUMANS AND
MOUSE. THIS WE GO OUT FURTHER WE ARE DIFFERENT FROM
BROCCOLI. BUT WHAT THIS MEANS IS THAT WE HAVE THREE
BILLION DNA BASE PAIRS, THAT MEANS THERE ARE ABOUT THREE MILLION DIFFERENCES BETWEEN EACH
PAIR OF HUMANS. SO A TREMENDOUS RESERVOIR OF GENETIC VARIATION
THAT ACCOUNTS FOR THE DIVERSITY THAT WE SEE. HOW MUCH DO POPULATIONS DIFFER?
THAT IS THE FIRST AREA THAT WE LOOK AT THIS MORNING.
HERE WE SEE A MAP OF THE WORLD WITH THE POPULATION THAT I'LL BE TALKING ABOUT DESIGNATED.
WE'VE BEEN TRYING TO SAMPLE MORE AND MORE EXTENSIVELY ACROSS THE WORLD AND IN COLLABORATION
WITH THE FOUNDATION IN SALT LAKE CITY WHO HAVE COLLECTED MORE THAN 100,000 DNA SAMPLES
FROM ALL OVER THE WORLD. I'M GO STEMMING YOU ABOUT VARIATION IN A THOUSAND
INDIVIDUALS REPRESENTING 40 POPULATIONS. REALLY QUITE DIVERSITY.
HERE ARE SOME OF THE PHOTOGRAPHS OF SOME OF THE TALKS I'LL BE TELLING YOU ABOUT.
TO ASSESS VARIATION THE STANDARD APPROACH IS TO LOOK AT ALLELE FREQUENCIES.
IF WE IMAGE IN THAT WE HAVE THREE SNPS SINGLE NUCLEOTIDE POLYMORPHISMS THAT WE'RE ANALYZING.
WE CAN SEE THAT THERE ARE DIFFERENCES IN THE FREQUENCIES OF THESE THREE SNPS IN POPULATIONS
ONE, TWO AND THREE. WE LOOK AT THOSE DIFFERENCES, WE LOOK AT THAT
VARIATION TO ASSESS PATTERNS OF SIMILARITY AMONG POPULATIONS.
THIS IS ONE OF TWO EQUATIONS THAT I'LL SHOW YOU.
I'M NOT GOING TO TORTURE YOU WITH MATHEMATICS THIS MORNING THIS IS PRETTY SIMPLE.
IT SHOWS HOW WE ESTIMATE A STATISTIC CALLED FST TO ASSESS VARIATION BETWEEN POPULATION.
SO, FST IS THE AMOUNT OF GENETIC VARIATION THAT IS DUE TO POPULATION DIFFERENCES.
AND WE GET IT BY LOOKING AT THE TOTAL HETEROZYGOCITY. TOTAL VARIATION ACROSS OUR SAMPLES, THAT'S
H SUB2. FROM THAT TOTAL WE SUBTRACT THE AVERAGE HETEROZYGOCITY
WITHIN EACH SUBDIVISION. IF FST IS ZERO ALL OF THE VARIATION THAT WE
AB EVERYBODY DAB DAB OBSERVE ARE IN POPULATIONS, THE AVERAGE WITHIN SUBDIVISIONS IS EQUAL TO
THE TOTAL. THERE'S NO DIFFERENCE BETWEEN POPULATION.
THE OTHER HAND IF FST IS ONE, THEN ALL OF THE VARIATION EXISTS BETWEEN POPULATIONS.
ONLY WAY WE CAN GET THIS WOULD BE FOR H TO BE ZERO.
IN OTHER WORDS ALL OF OUR POPULATION OR IN THIS CASE CONTINENTS WOULD CONSIST OF IDENTICAL
CLONE. NO VARIATIONS WITHIN SUBDIVISIONS.
FST OF ONE, MAXIMUM VARIATION BETWEEN SUBDIVISIONS, FST OF ZERO, NONE.
IF WE LOOK AT THIS STATISTIC IN SERIES OF POLYMORPHISMS IN THE SAMPLES, IF WE LOOK AT
STRS, RESTRICTION SITE POLYMORPHISMS AND L1S AND 250K SNP ARRAY WE SEE THAT THE FST VALUE
FOR OUR HUMAN POPULATION IS PRETTY CONSISTENTLY SOMEWHERE BETWEEN 10-15%.
THIS WE SEE IN MANY STUDIES DIFFERENT KINDS OF DNA POLYMORPHISMS, DIFFERENT SETS OF POPULATIONS,
BUT TYPICALLY ROUGHLY 10 TO 15% OF GENETIC VARIATION CAN BE ASCRIBED TO DIFFERENCES BETWEEN
THESE MAJOR POPULATIONS. THAT'S RELATIVELY SMALL AMOUNT.
TELLING US THAT THERE ISN'T THAT MUCH VARIATION BETWEEN HUMAN POPULATIONS OR THESE LARGELY
NEUTRAL DNA VARIANT. WE CAN COMPARE THAT WITH SKIN PIGMENTATION.
, WE SEE THE OPPOSITE PATTERN. 90% OF VARIATION EXISTS BETWEEN POPULATION.
VERY DIFFERENT PATTERN FROM WHAT WE LOOK AT ACTUAL DNA VARIATION.
THESE ARE TRAITS, THIS IS STRONGLY SELECTED IN HUMAN POPULATION FOR DIFFERENT AND DIVERGENT.
IF WE LOOK AT THE THREE HAPMAP POPULATIONS OF THE EUROPEAN DERIVED POPULATIONS, THE TWO
ASIAN POPULATIONS WE JUST LOOK AT THOSE, THAT'S A LIMITED SAMPLE OF HUMAN DIVERSITY.
GIVES US A HIGH FST VALUE ABOUT 15%. IF WE START TO SAMPLE MORE POPULATIONS OF
FST TENDS TO GO DOWN THAT IS LESS VARIATION BETWEEN POPULATIONS AS WE SAMPLE MORE OF THE
WORLD'S DIVERSITY. HERE LOOKING AT 27 POPULATIONS PST HAS GONE
DOWN. THE IMPORTANCE IMPORTANT AS WE SAMPLE MORE
EVENLY ACROSS THE GLOBE THIS LEVEL OF DIFFERENTIATION TENDS TO GO DOWN.
IT'S NOT GOING TO ZERO BECAUSE OF COURSE THERE IS VARIATION AMONG HUMAN POPULATION.
BUT IMPORTANTLY IN THE OVERESTIMATED IF WE SAMPLE SELECTIVELY.
ASK, WHAT PROPORTION OF SNP ARE SHARED AMONG POPULATIONS.
HERE WE'RE LOOKING AT COMMON SNPS FROM THE ENCODE DATABASE WHERE THE MINOR ALLELE FREQUENCY
IS GREATER THAN 5%. ABOUT 80% OF THE MINOR ALLELE ARE SHARED AMONG
THE THREE MAJOR CONTINENTAL POPULATIONS. FEWER THAN 1% ARE SEEN JUST IN ASIAN POPULATION
AND FEWER THAN 1% ARE RESTRICTED JUST TO EUROPEAN POPULATION.
ABOUT 6% ARE SPECIFIC TO AFRICAN POPULATION. MORE DIVERSITY INNERVE CAN AND DIVERSITY OUTSIDE
OF AFRICA BEING LARGELY SUBSET OF WHAT WE SEE IN AFRICA.
THIS PAPER JUST CAME OUT TWO, COMPLETE AFRICAN GENOMES.
YOU CAN SEE AGAIN COMPARING THOSE GENOMES, NOW LOOKING AT WHOLE GENOME SEQUENCES SO THIS
INCLUDES NOT JUST COMMON VARIANTS BUT ALSO RARE VARIANTS, WE CAN SEE THAT STILL AS WE'RE
COMPARING THE INDIVIDUALS THERE'S STILL A LOT OF SHARING OF VARIANTS AMONG THESE INDIVIDUALS
EVEN LOOKING AT RARE VARIANTS. NOT AS MUCH SHARING WHEN WE'RE LOOKING AT
COMMON, BECAUSE THE COMMON VARIANTS TEND TO BE OLDER MORE LIKELY TO BE SHARED.
BUT STILL INTERESTING LEVEL OF DNA SHARING AMONG THESE INDIVIDUALS FOR WHOM WE NOW HAVE
COMPLETE GENOME SEQUENCE. HOW DO WE ASSESS GENETIC DISTANCE DIFFERENCES
BETWEEN POPULATION. WE CAN DO SIMPLE GENETIC DISSTANCES.
WE DEFINE THE DISTANCE BETWEEN TWO POPULATIONS, CALL THEM I AND J BY THE DIFFERENCE IN ALLELE
FREQUENCIES. PIECE OF I AND PIECE OF J ARE THE ALLELE FREQUENCIES
IN THE TWO POPULATIONS. WE GO BACK TO THE FREQUENCIES I SHOWED YOU.
WE HAVE THREE. WE'RE LOOKING AT THREE SNPS.
IF WE WANT TO ASSESS THE DISTANCE BETWEEN POPULATIONS ONE AND TWO WE CAN SIMPLY FOR
THIS SNP, SNP ONE, SUBTRACT THE DIFFERENCE IN THEIR FREQUENCIES IN POPULATIONS 1 AND
2 THAT'S VERY SIMPLE GENETIC DISTANCE ESTIMATE. THEN TO GET THE OVERALL DISTANCE BETWEEN POPULATIONS
1 AND 2 WE WOULD JUST AVERAGE THIS DISTANCE WITH THE OTHER -- DISTANCES DERIVED FROM THE
OTHER TWO SNPS. IT'S REALLY PRETTY SIMPLE.
ON AVERAGE HOW DIFFERENT ARE THESE POPULATIONS IN TERMS OF THEIR ALLELE FREQUENCY F. THAT
WE CAN BUILD A NETWORK OF SIMILARITY AMONG POPULATIONS.
WE HAVE OUR THREE POPULATIONS, WE HAVE OUR DISTANCE.
WE CAN DRAW A NODE BETWEEN THOSE TWO POPULATIONS, THEN WE CAN TAKE THE AVERAGE OF SAYS SUBTRACT
THAT FROM THE FREQUENCY IN THE THIRD POPULATION THAT GIVES US ANOTHER NODE IN OUR NETWORK.
THAT THE HOW WE SHOW THE THEM IN TERMS OF ALLELE FREQUENCIES.
JUST BY LOOKING AT THEM ARE A LITTLE MORE SIMILAR TO EACH OTHER THAN THEY ARE TO POPULATION
THREE. THAT'S WHAT THE NETWORK DISPLAYS FOR US F.
WE DO THIS NOW FOR SERIES OF POPLY MORPHISMS NOW LOOKING AT ALU INSERTION POLYMORPHISMS.
THOSE ARE SHORT INTERSPERSED NUCLEAR ELEMENTS THAT INSERTED RECENTLY IN TO THE HUMAN GENOME
SOME PEOPLE WILL HAVE AN ALU AT SPECIFIC CHROMOSOME LOCATION, OTHERS DON'T.
THEN WE'RE ASSESS THE FREQUENCIES OF THOSE, IN THIS CASE 100ALU POLYMORPHISMS, WORK WE
DID A FEW YEARS AGO AND WE'RE LOOKING AT VARIOUS HUMAN POPULATION.
YOU SEE SOME INTERESTING PATTERNS HERE, FIRST OF ALL YOU SEE THAT POPULATION DO TEND TO
GROUP TOGETHER ACCORDING TO THEIR CONTINENT OF ORIGIN.
THIS ISN'T REALLY A SURPRISE, THEY ARE MORE LIKELY TO HAVE COMMON HISTORY THERE IS A CORRELATION
BETWEEN ANCESTRY AND GEOGRAPHIC LOCATION. SO, WE CAN SEE POPULATIONS FROM MAJOR CONTINENTS,
ESSENTIALLY GROUPING TOGETHER. THE OTHER THING WE NOTICE HERE IS THAT THERE'S
A LOT MORE DIVERSITY AMONG THE AFRICAN POPULATION THAN IN THE REST OF THE WORLD.
WE'LL COME BACK TO THAT. IF I WOULD ASSESS THE STATISTICAL SIGNIFICANCE
OF THESE RESULTS, THEE ARE BOOTSTRAP SUPPORT LEVELS THEY'RE VERY HIGH TELLING US THAT THESE
GROUPINGS HAVE SUBSTANTIAL STATISTICAL SUPPORT. A SIMILAR NETWORK ONLINE ONE INSERTION POLYMORPHISMS
WE SEE THE SAME PATTERN. NETWORK BASED ON A 250K ARRAY, AGAIN WE SEE
THAT SAME PATTERN. HERE ARE SERIES OF AFRICAN POPULATIONS, EUROPEAN
POPULATIONS, SERIES FROM SOUTH ASIA, EAST ASIA.
AND NEW WORLD OVER HERE IN YELLOW. SO THESE POPULATIONS DO TEND TO GROUP TOGETHER
ACCORDING TO THEIR GEOGRAPHIC LOCATION. NOW ADDED THE HDGP SAMPLES.
ANOTHER 40 POPULATIONS WE SEE AGAIN THE SAME PATTERN.
IT'S REALLY QUITE ROBUST. THIS IS ANOTHER ANALYSIS PUBLISHED IN "NATURE"
A COUPLE YEARS AGO BY ANOTHER GROUP, SOMEWHAT DIFFERENT SAMPLE OF POPULATIONS LOOKING BOTH
AT CNBS AND SNPS AND WE SEE THE SAME PATTERNS, WE ASSURING LEVEL OF CONSISTENCY ACROSS STUDIES.
IF WE PLOT HAPLOTIGHT HETEROZYGOCITY. WE'RE SAYING, HOW MUCH VARIATION IN HAPPEN
LAY TIGHT IS THERE ACROSS THE -- HAPLOTIGHT ACROSS THE WORLD AS IT RELATES IN DISANSWER
FROM EAST AFRICA. WHAT WE AUTO IS A HAPLOTIGHT DIVERSITY STEADY
DECLINES AS WE GO FURTHER AWAY FROM.
FIRST AROSE IN AFRICA THAT IS AN TOPICALLY MODERN HUMAN, PEOPLE THAT LOOK LIKE US AROSE
ROUGHLY 200,000 YEARS AGO STAYED IN AFRICA AT LEAST 100O YEARS, DEVELOPED -- 100,000
YEARS, DEVELOPED VARIATION THEN SMALL SUBSET WENT OUT TO COLONIZE THE REST OF THE WORLD.
AS A RESULT OF THAT VARIATION IN THE REST OF THE WORLD TENDS TO BE LESS THAN IN AFRICA
TENDS TO BE SUBSET OF WHAT WE SEE IN AFRICA. ALL VERY CONSISTENT WITH THE RECENT AFRICAN
ORIGIN OF OUR SPECIES AND A COMMON ORIGIN OF OUR SPECIES.
THIS IS A DIFFERENT TAKE ON HUMAN ORIGINS. I WAS IN THE SUPERMARKET A FEW YEARS AGO AND
MY EYES WERE CAUGHT BY THIS HEADLINE "ADAM AND EVE SKELETON HAD BEEN STOLEN" I WASN'T
AWARE THEY HAD BEEN STOLEN, BECAUSE I WAS PROMISED MORE AMAZING PHOTOS INSIDE, I HAD
TO BUY IT. WHAT I DISCOVERED, ALL THAT'S LEFT IS EVE'S
LEGS AND THE IDENTITY OF THE PERPETRATOR MAY HAVE BEEN ESTABLISHED.
INEVITABLY IF WE'RE TALKING ABOUT DIFFERENCES AMONG POPULATIONS, AMONG INDIVIDUALS, THE
ISSUE OF RACE COMES UP. WHAT DOES GENETICS NOW TELL US ABOUT TRADITIONAL
CONCEPTS OF HUMAN RACE. I THINK WHAT YOU'LL SEE IS THAT OUR VIEW OF
RACE MUCH MORE COMPLEX AS WE BEGIN TO LOOK AT GENETIC DATA.
FIRST WE CAN ASK THE QUESTION, WHY DOES RACE EVEN MATTER?
WHY DOES IT KEEP COMING UP IN OUR DISCUSSION? WELL, CERTAINLY THE PREVALENCE OF MANY DISEASES
IS KNOWN TO VARY BY POPULATION AND ALONG LINES THAT CORRESPOND TO TRADITIONAL RACIAL DESIGNATIONS,
THINGS LIKE PROSTATE CANCER, HYPERTENSION. WE KNOW THAT SOME RELATIVELY COMMON DISEASE
PREDISPOSING VARIANTS VARY AMONG POPULATIONS. THINGS LIKE CLOTTING FACTOR V L,IDEN VARIANT.
SUBSTANTIALLY MORE COMMON AMONG EUROPEANS THAN AMONG OTHER INDIVIDUALS.
THERE'S EVIDENCE RESPONSE TO SOME DRUGS MAY VARY AMONG POPULATION.
AFRICAN-AMERICANS MAY ON AVERAGE BE LESS RESPONSE SIEVE TO ACE INHIBITORS, BETA BLOCKERS AND
I EMPHASIZE "MAYBE" BECAUSE WE COME BACK TO THAT POINT AND WHAT THAT MEANS.
IN THE FORENSIC DATABASES THAT ARE COMMONLY USED BY THE FIB AND BY CRIME LABS THEY ARE
GROUPED ALONG TRADITIONAL, QUOTE, RACIAL, LINES.
THESE
DESIGNATIONS ARE USED COMMONLY IN MANY WAYS. THE QUESTION IS, WHAT CAN GENETICS TELL US
ABOUT THEIR VALIDITY. IT'S INTERESTING TO LOOK AT SOME COMMENTS
OVER THE LAST DECADE ON RACE. THERE WAS EDITORIAL IN THE "NEW ENGLAND JOURNAL"
THAT ASSERTED THAT RACE IS BIOLOGICALLY MEANINGLESS. IN A RESPONSE TO THE "NEW YORK TIMES" A PSYCHIATRIST
DR. SATEL RESPONDED "I AM A RACIALLY PROFILING DOCTOR."
DELIBERATELY PROVOCATIVE COMMENT, POINT WAS THAT SHE USES POPULATION AFFILIATION TO HELP
DECIDE DOSAGE AND DRUGS FOR HER PATIENTS. THE STATEMENT A FEW YEARS FROM THE AMERICAN
ANTHROPOLOGIC ASSOCIATION THAT "ANY TWO INDIVIDUALS WITHIN A PARTICULAR POPULATION ARE AS DIFFERENT
GENETICALLY AS ANY TWO PEOPLE SELECTED FROM ANY TWO POPULATIONS IN THE WORLD."
WE'LL SEE WHAT THE GENETIC DATA ACTUALLY DO TELL US.
WHEN THERE ARE SO MANY DIVERGENT OPINIONS ON AN ISSUE IT'S TIME TO LOOK AT DATA.
THE COVER OF "SCIENTIFIC AMERICAN" A FEW YEARS AGO ASKED, DOES RACE EXIST?
AND THIS IS THE PART THAT CAUGHT MY ATTENTION. SCIENCE HAS THE ANSWER.
ANY TIME AS A SCIENTIST I THINK WHEN WE SEE THAT "SCIENCE HAS THE ANSWER" WE GET SKEPTICAL.
LET'S LOOK AT THE DATA. WE TABULATE DNA SEQUENCES AMONG INDIVIDUALS.
NOW INSTEAD OF LOOKING AT POPULATION WE LOOK AT INDIVIDUALS.
WE CAN PICK A FEW INDIVIDUALS WHOSE DNA SEQUENCE WE HAVE HYPOTHETICALLY OBTAINED.
WE'RE LUBING AT GEORGE BUSH, JOHN MCCAIN, HILLARY CLINTON I COULDN'T RESIST PUTTING
IN JOHN EDWARDS. I'M NOT SURE IF ANYONE WANTS TO SHARE DNA
WITH JOHN EDWARDS THESE DAYS BUT WE CAN COMPARE THEIR SEQUENCES.
SO AS WE'RE MAKING THESE DNA NETWORKS WHAT WE'RE INTERESTED IN IS SEQUENCE DIFFERENCE
AMONG OUR PAIRS OF INDIVIDUALS. IF WE COMPARE BUSH AND MCCAIN, WE SEE THAT
THERE ARE TWO SEQUENCE DIFFERENCES. WE PUT A TWO IN OUR MATRIX BETWEEN BUSH AND
MCCAIN F. WE COMPARE BUSH AND CLINTON WE SEE THAT THERE ARE FIVE DIFFERENCES.
WE PUT A FIVE HERE. BUSH AND EDWARDS, SIX.
EDWARDS AND MCCAIN, FOUR. SO FORTH.
WE MAKE A MATRIX OF DNA DIFFERENCES AMONG OUR PAIRS OF INDIVIDUALS.
FROM THAT WE CAN MAKE A DIAGRAM OR TREE THAT SHOWS HOW SIMILAR THEY ARE.
THIS IS HYPOTHETICAL. IT GIVES YOU DISPLAY THEN OF DISTANCES --
DIFFERENCES AMONG OUR PAIRS OF INDIVIDUALS. IF WE'RE LOOKING AT JUST A FEW PEOPLE WE CAN
EASILY LOOK AT THE MATRIX ITSELF AND SEE THE PATTERN.
BUT IMAGINE LOOKING AT HUNDREDS OR EVEN THOUSANDS OF INDIVIDUALS THEN IT BECOMES MUCH MORE DIFFERENT
BY LOOKING AT THE MATRIX OF A THOUSAND BY A THOUSAND.
THESE DISPLAYS HELP US TO SEE THE PATTERN VERY EASILY.
STEVE WHO WORKS WITH US FEW YEARS AGO SAW THIS MATRIX IN THE "NEW YORK TIMES," MATRIX
OF PERCENT DISAGREEMENT AMONG THE NINE SUPREME COURT JUSTICES.
HE WAS LEARNING POPULATION GENETICS AT THIS TIME HE THOUGHT THIS WAS GOOD EX ARE SIGHS.
IF YOU LOOK AT THIS MATRIX YOU CAN SEE SOME PATTERNS, YOU CAN SEE FOR EXAMPLE THAT JUSTICES
THOMAS AND SCALIA HAVE ONLY 9% DISAGREEMENT. PRETTY SIMILAR.
BUT STILL IT'S NOT SO EASY TO DEDUCE THE WHOLE PATTERN UNTIL YOU MAKE A DIAGRAM.
A TREE THEN YOU CAN SEE THE PATTERN VERY EASILY. WE HAVE THE CONSERVATIVE WING OF THE COURTS
HERE. THE OTHER WING OF THE COURT OVER HERE SHOWING
UP VERY NICELY ON THIS DISPLAY. IF WE DO THE SAME THING AT AT DNA, WE'RE LOOKING
A THE ANGIOTENSINOGEN GENE. WE LOOKED AT 14BK, HOW SIMILAR BE THE MEMBERS
OF THESE CONTINENTAL POPULATIONS, ASIAN, EUROPEANS AND AFRICANS.
WHAT WE'VE SEEN IS THAT SOMETIMES AN INDIVIDUAL FROM AFRICA IS ACTUALLY MORE SIMILAR TO PEOPLE
FROM ASIA OR PEOPLE FROM EUROPE THAN TO OTHERS FROM AFRICA.
WHEN WE'RE LOOKING AT THIS SINGLE GENE. LOOKING AT 14KB OF SEQUENCE.
WHAT THAT IS REFLECTING IS THE MIXED ANCESTRY OF INDIVIDUALS WITH REGARD TO SPECIFIC GENES.
OUR COMPLEX HISTORY OF MIGRATION AND MIXED, WE SEE WITHIN WE LOOK AT HUMANS, WE SEE GENES
FROM EUROPE AND AFRICA. WE SEE GENES FROM ASIA AND EUROPE.
WE HUMANS DO HAVE A MIXED AND VERY COMPLEX HISTORY OF MIGRATION THERE.
IS NO SUCH THING AS A QUOTE, PURE, HUMAN POPULATION. GENETIC DATA TELLS US THAT VERY CLEARLY.
CARL DARWIN SAID THAT IT MAY BE DOUBTED WHETHER ANY CHARACTER CAN BE NAMED WHICH IS DISTINCTIVE
OF A RACE AND IS CONSTANT. SO, DARWIN WAS WELL AWARE OF IT.
THAT CHARACTERS THAT HE WAS LOOKING AT TENDED TO VARY IN FREQUENCY AMONG POPULATION BUT
SELDOM COULD YOU DEFINE POPULATION BASED ON ANY GIVEN CHARACTERISTIC.
NOW, HERE IS WHAT WE DID A FEW YEARS AGO WAS TO LOOK AT LARGER NUMBER OF VARIANTS, IN THIS
CASE, ALU, STR AND RESTRICTION SITE POLYMORPHISMS, CLOSE TO 200 POLYMORPHISMS ASKED THE SAME
QUESTION. HOW SIMILAR ARE THESE INDIVIDUALS IF NOW INSTEAD
OF LOOKING AT SEQUENCE FROM ONE GENE WE'RE LOOKING AT 190 INDEPENDENT VARIANTS.
NOW WE SEE THAT THERE IS SOME PATTERN HERE WHERE OUR SAMPLES FROM ASIA TEND TO GROUP
TOGETHER FROM, EUROPE GROUP TOGETHER, AFRICA, GROUP TOGETHER, WE'RE USING A LOT MORE INFORMATION
WE'RE PICK UP MORE ABOUT THE ANCESTRIES OF -- ANCESTRYS OF THESE INDIVIDUALS NOTICE
THAT THESE BRANCHES MOST OF THE BRANCH LENGTH IS SEEN WITHIN POPULATION.
THIS IS CONSISTENT WITH THE FST STATISTICS THAT SAID MOST OF THE VARIATION WE SEE, WE
SEE WITHIN MAJOR POPULATIONS. BUT THERE IS ENOUGH VARIATION JUST ENOUGH
BETWEEN POPULATIONS SO THAT IF WE'RE LOOKING AT A LOT OF CHARACTERS WE CAN BEGIN TO SEE
A REFLECTION OF PARTIAL ISOLATION OF THESE POPULATIONS THROUGH THEIR HISTORY.
THE ANALOGY I LIKE TO USE IS LET'S SAY HEIGHT F. WE ONLY LOOK AT HEIGHT, WE'RE GOING TO
SEE QUITE A LOT OF OVERLAP BETWEEN OUR MALE AND FEMALE POPULATION.
IF WE ADD ANOTHER CHARACTERISTICS, LET'S SAY WAIST/HIP RATIO NOW WE HAVE MORE INFORMATION
THAT ALLOWS US TO DISCERN MALES VERSUS FEMALES. AND SO THERE'S LESS OVERLAP BETWEEN THEM.
THAT'S WHAT WE'RE DOING AS WE LOOK AT MORE GENETIC CHARACTERS WE'RE LEARNING MORE ABOUT
ANCESTRYS OF THESE INDIVIDUALS, STARTING TO SEE MORE OF THE NONOVERLAPPING PART OF THOSE
CIRCLES I SHOWED YOU. IF WE DO THIS WITH A LARGER NUMBER OF CHARACTERS,
WE ARE USING A SNP ARRAY WE START TO SEE A PATTERN IN THIS DIAGRAM OF INDIVIDUALS.
DON'T WORRY ABOUT READING THE LABELS, THEY CORRESPOND TO POPULATIONS SO THAT IF WE USE
LARGE NUMBER OF SNPS ACROSS THE HUMAN GENOME WE START TO SEE INDIVIDUALS SORTING ACCORDING
TO THEIR POPULATION OF ORIGIN. NOW, SHY POINT OUT THESE POPULATIONS ARE PRETTY
WELL SEPARATED FROM EACH OTHER GEOGRAPHICALLY. BUT WE DO SEE, FOR EXAMPLE, AFRICAN POPULATIONS
HERE, EUROPEAN POPULATION, SOUTH INDIAN POPULATION. SOUTH PACIFIC, NEW WORLD, ASIAN, SO FORTH.
IS THERE ORDER OF ANCESTRY IF WE LOOK AT LOTS OF INDEPENDENT DNA CHARACTERS.
RECENTLY MY COLLEAGUE IN MY DEPARTMENT LOOKED AT THE WHOLE GENOME SEQUENCE DATA, NOW PUBLICLY
AVAILABLE FOR TEN INDIVIDUALS. IF WE LOOK AT WHOLE SEQUENCE DATA WE SEE THAT
AGAIN INDIVIDUALS TEND TO SORT OUT ACCORDING TO CONTINENT OF ORIGIN.
WHICH IS NOT TOO SURPRISING IF WE DOCK THIS WITH 10K -- 10,000 SNPS WE EXPECT IF WE LOOK
AT WHOLE SEQUENCE DATA WE'RE GOING TO SEE A SIMILAR PATTERN.
NOW, ANOTHER THING THAT MARK FOUND THAT I THINK IS PRETTY INTERESTING IS THAT THERE
IS SOME VARIATION DEPENDING ON THE SEQUENCING PLATFORM THAT IS USED.
THESE ARE THE SAME AFRICAN SAMPLE BUT LOOK DIFFERENT DEPENDING WHERE -- THERE WERE 557,000
DIFFERENCES BETWEEN THEM GENERATED BY DIFFERENCES IN PLATFORMS.
ALTHOUGH THERE IS CONSISTENCY HERE WITH ANCESTORS, THERE IS ALSO PLATFORM VARIATION THAT WE SEE
IN OUR DIAGRAM. YOU MIGHT SAY, WELL, WHAT IS WHOLE GENOME
SEQUENCE TELLING US THAT WE CAN'T GET WITH JUST A SAMPLE OF SNP.
THIS IS VERY NEW STUDY, JUST CAME OUT WHERE WE WERE ABLE, ONE OF MY POST DOCS WAS ABLE
TO USE THE PRESENCE OF ALU INSERTIONS IN WHOLE SEQUENCE DATA TO MARK REGIONS OF THE GENOME
THAT ARE ANCIENT. HE COMPARED THE PUBLISHED NIH SEQUENCE WITH
THE HUREF. THE IDEA HERE IS THAT IF WE LOOK AT WHOLE
SEQUENCE VARIATION, THE AVERAGE TIME FOR ANY GENOMIC REGION ACROSS THESE TWO GENOMES THEY
WOULD HAVE COMMON ANCESTOR ABOUT 460,000 YEARS AGO.
BUT, BECAUSE ALU INSERTIONS ARE RARE EVENTS, ONLY OCCUR IN ONE IN 20 BIRTHS, THEY ARE TEND
TO BE PRESERVED JUST IN VERY OLD REGIONS OF THE GENOME.
BECAUSE THEY ARE SO RARE, IN OTHER WORDS, BETWEEN MY BROTHER AND ME THERE'S VERY LITTLE
CHANCE THAT WE HAVE -- THAT I WOULD HAVE ALU INSERTION ON SPOT ON CHROMOSOME FIVE THAT
HE DOESN'T HAVE. BECAUSE THESE ARE RARE EVENTS THEY MARK ANCIENT
PARTS OF THE GENOME WHERE ACTUALLY THE AVERAGE COALESCENESS TIME IS ABOUT 900,000 YEARS.
FOR THESE REGIONS OF THE GENOME, REGIONS IN WHICH AN ALU HAS INSERTED THEY TEND TO BE
VERY OLD WE CAN LOOK AT SEQUENCE VARIATION IN THOSE REGIONS, TO PROBE VERY ANCIENT HISTORY
IN OUR SPECIES AND IN OUR ANCESTORS. WHAT CHAD WAS ABLE TO DO, THIS PAPER WAS JUST
PUBLISHED IN JANUARY, ACTUALLY THEY ESTIMATE THE EFFECTIVE POPULATION SIZE OF HUMAN ANCESTORS,
1.2 MILLION YEARS AGO. WHAT'S INTERESTING IS THAT THAT ESTIMATE IS
ONLY ABOUT 18,000. WE AT THAT TIME OUR ANCESTORS PREHUMAN ANCESTORS
HAD VERY SMALL POPULATION. EFFECTIVE SIZE OF ANATOMICALLY MODERN HUMANS
IS QUITE SMALL BUT THAT SUGGESTS THAT OUR ANCESTORS WERE FAIRLY CLOSE TO EXTINCTION
AT ONE POINT IN THEIR HISTORY. WHAT I FIND REMARKABLE IS THAT WE CAN LEARN
THIS, LEARN IT WITH QUITE A LOT OF PRECISION FROM JUST TWO HUMAN DNA SEQUENCES.
BECAUSE WITH WHOLE GENOME SEQUENCE WE HAVE A LOT OF INFORMATION.
WE CAN MAKE ESTIMATES LIKE THIS THAT WOULD BE IMPOSSIBLE WITHOUT THAT MUCH INFORMATION,
WITHOUT THAT MUCH VARIATION IS LOOK AT. SO, LOT OF INTERESTING THINGS THAT WE DOCK
WITH THESE WHOLE GENOME SEQUENCES AND WE'RE VERY HAPPY THAT THEY ARE PUBLICLY AVAILABLE
SO THAT WE CAN ALL LOOK AT THEM AND THINK OF INTERESTING THINGS TO DO WITH THEM.
HERE IS ANOTHER WAY OF LOOKING AT GENETIC DISTANCES AMONG POPULATIONS AT SIMILARITIES
AND DIFFERENCES. THIS IS CALLED A PRINCIPLE COMPONENT ANALYSIS.
USED VERY COMMONLY IN POPULATION GENETICS. I WON'T GO IN TO DETAILS ABUT THIS, BUT BASICALLY
WHAT IT DOES IS DISPLAYS DIFFERENCES AMONG OUR INDIVIDUALS, IN THIS CASE IN THREE DIMENSION.
THEN THIRD ONE THIS IS KIND OF THE THIRD DIMENSION -- THE POINT SHEER THAT IF WE LOOK AT ONLY
TEN SNPS, WE LOOK AT SMALL COLLECTION OF VARIATION ACROSS THE GEE NO, MA'AM WE CAN'T REALLY SEE
-- GENOME, WE CAN'T SEE MUCH OF A PATTERN, WOE DON'T HAVE VERY MANY CHARACTERS, THERE'S
A LOT OF OVERLAP. IF WE LOOK AT 100 SNPS IN THE SAME INDIVIDUALS
THIS SAME KIND OF DISPLAY WE SEE A PATTERN BUT STILL GREAT DEAL OF OVERLAP NOT REALLY
A DISCERNIBLE PATTERN HERE IN THREE DIMENSIONS. IF WE LOOK AT A THOUSAND SNPS WE START TO
SEE SOME DISCERNIBLE PATTERN. IN FACT THESE GROUPS CORRESPOND TO THE MAJOR
CONTINENTAL POPULATION. 23 WE LOOK AT 250,000 SNPS THERE'S EVEN MORE
OF A PATTERN. WE CAN BEGIN TO SEE INDIVIDUALS SORTING IN
TO POPULATIONS, FROM INDIA HERE, ASIAN POPULATIONS, EUROPEAN, AFRICAN POPULATIONS.
AGAIN WITH LOTS OF INFORMATION WE CAN START SEE INDIVIDUALS SORTING IN TO POPULATIONS
OF ORIGIN. THE HAPMAP FITS WHERE WE WOULD EXPECT THEM
TO. IF YOU TRANSLATE THESE DIMENSIONS THE FIRST
ONE IS SORT OF AFRICA VERSUS NON-AFRICA, SO THIS IS SORT OF THE OUT OF AFRICA DIMENSION
OF THIS PLOT. THE SECOND ONE IS PRETTY MUCH EAST-WEST ACROSS
THE OLD WORLD AND THIRD ONE IS NORTH-SOUTH ORIENTATION.
IT GIVES US THREE DIMENSIONS OF HUMAN GENETIC VARIATION.
THIS IS SIMILAR PLOT LOOKING AT 850 INDIVIDUALS IN TWO DIMENSIONS WE HAVE ESSENTIALLY GOING
FROM WEST TO EAST. AGAIN WE SEE INDIVIDUALS SORTING OUT BUT I
ALSO WANT TO POINT OUT THAT THERE IS OVERLAP. WE CAN'T, ESPECIALLY NOW THAT WE'RE SAMPLING
MORE BROADLY COULDN'T DRAW SHARP BOUNDARY AMONG THESE VARIOUS POPULATIONS.
THAT'S VERY IMPORTANT POINT. HERE WE'RE LOOKING AT EURASIA ALONE.
YOU START SEE A MAP OF THE WORLD AS YOU LOOK AT THESE POPULATIONS, AS YOU LOOK AT THEIR
GENETIC SIMILARITIES FOR 250,000 SNPS. IMPORTANT POINT SHEER THAT IF WE LOOK AT MULTIPLE
POLYMORPHISMS, WE LOOK AT 10,000 OR 100,000 OR A MILLION POLYMORPHISMS WE CAN WITH SOME
ACCURACY PREDICT POPULATION AFFILIATION BECAUSE THESE SNPS, IF THERE ARE MANY OF THEM, ARE
AS I SAID TELLING US ABOUT THESE NONOVERLAPPING PARTS OF THE CIRCLES.
BUT WHAT WE CAN'T DO, THIS IS A CRITICAL POINT, WE CAN'T GO THE OTHER WAY.
BECAUSE THESE SNPS VARY JUST IN FREQUENCY AMONG POPULATIONS.
WE CAN'T BY LOOKING AT A POPULATION AFFILIATION WE CAN'T INFER WHAT SOMEONE'S SNP ALLELE IS
GOING TO BE, OR CAN'T FROM A SINGLE SNP INFER POPULATION AFFILIATION.
THAT I THINK IS A CRITICAL POINT. WELLF WE HAVE ENOUGH GENETIC INFORMATION COULD
WE CLASSIFY EVERYBODY IN TO A POPULATION. LET'S LOOK AT THAT NETWORK THAT WE VIEWED
JUST A FEW MINUTES AGO, LET'S ADD AFRICAN-AMERICAN. SOME INDIVIDUALS GROUP IN TO THIS GROUP DOWN
HERE WITH PEOPLE FROM AFRICA. OTHERS DON'T REALLY FALL IN TO A GROUP.
IF WE LOOK AT PUERTO RICANS, ANOTHER GROUP WITH A COMPLEX HISTORY, SOME TEND TO FALL
IN WITH PEOPLE FROM SPAIN, OTHERS CLOSER TO PEOPLE FROM AFRICA.
THERE ARE MANY GROUPS, MANY HUMAN GROUPS THAT DON'T FALL NEATLY IN TO ANY OF THESE CATEGORIES.
AS WE SAMPLE THEM, AS WE LEARN MORE ABOUT THEM AS HUMAN MIGRATION CONTINUES TO INCREASE
WE'LL FIND THAT THERE ARE A LOT OF GROUPS, LOT OF INDIVIDUALS THAT DON'T FALL IN TO ANY
SPECIFIC GROUP. WE HAVE COMPLEX ANCESTORS.
THEN I THINK EMPHASIZES THE FALLACY OF THINKING TYPE LOGICALLY, THIS IS ONE OF THE REASONS
WHY I DON'T USE THE TERM "RACE" IN MY OWN PUBLICATIONS.
BECAUSE I THINK IT TENDS TO ENCOURAGE THINKING ALONG THE LINES OF TYPES AND TWPOLOGIES WHEN
IN FACT WE'VE SEEN MOST HUMAN GENETIC VARIATION IS SHARED AMONG POPULATIONS.
LET ME ASK YOU A QUESTION. WAYNE JOSEPH, GREW UP IN LOUISIANA IN A CREOLE
FAMILY. WHAT DO YOU THINK HIS ANCESTRY IS LOOKING
AT HIS APPEARANCE? ANY GUESSES?
FRENCH. YOU CAN TELL THIS IS A TRICK QUESTION, CAN'T
YOU? WELL, HE WAS RAISED AS AN AFRICAN-AMERICAN.
HE WAS HIGH SCHOOL PRINCIPAL IN CALIFORNIA, HE ISN'T HIS DNA OFF TO BE TESTED BY A COMPANY
TO FIND OUT ABOUT HIS ANCESTRY. NOW, I SHOULD SAY THIS WE HAVE TO I TAKE THESE
ANCESTRY ESTIMATES WITH A GRAIN OF SALT, A NUMBER OF ASSUMPTIONS INVOLVED BUT WHAT HE
GOT BACK WAS THAT HE WAS 57% EUROPEAN, 39% NATIVE AMERICAN, 4% EAST ASIAN APPARENTLY
NO AFRICAN GENES AT ALL. DESPITE HIS SELF REPORTED ANCESTRY.
HE RETAINED HIS CULTURE, OF COURSE. BUT IT'S INTERESTING TO SEE HOW ONE SELF REPORTED
ANCESTRY CAN DIFFER COMPLETELY FROM ONE DNA MEASURED ANCESTRY.
AT LEAST AS ACCURATE AS THAT IS. THIS POINTS OUT VERY IMPORTANT DIFFERENCE.
IN OUR DISCUSSION ABUT RACE THE DIFFERENT BETWEEN INDIVIDUAL ANCESTRY WHICH CAN BE VERY
COMPLEX AND RACE WHICH IS VERY BLUNT TOOL. AN INDIVIDUAL WITH 90ERS AFRICAN ANCESTRY,
10% EUROPEAN ANCESTRY WOULD BE CONSIDERED AFRICAN AMERICAN IN THE UNITED STATES.
ALSO AN INDIVIDUAL WITH ONLY SAY 30 OR 40% AFRICAN ANCESTRY IN THE UNITED STATES WOULD
LIKELY SELF IDENTIFY AS AFRICAN AMERICAN. EVEN THOUGH THEIR GENETIC CONSTITUTION VERY
DIFFERENT. THAT'S WHY I THINK IT'S SO IMPORTANT TO UNDERSTAND
THIS DIFFERENCE BETWEEN INDIVIDUAL ANCESTRY AND WHAT WE REFER TO AS RACE.
A FEW AGO I SENT MY DNA IN TO A COMPANY TO LEARN SOMETHING ABOUT MY OWN ANCESTRY.
I WAS REALLY DISAPPOINTED, THIS IS ABOUT AS BORING A GENOME AS YOU CAN FIND, ACCORDING
TO THE COMPANY, AT LEAST. MY ANCESTRY WAS 100% EUROPEAN, WITH NO INTERESTING
VARIATION WHATSOEVER. I SHOULD SAY, ALL MY GRANDPARENTS CAME FROM
NORWAY BUT I WAS HOPING THERE MIGHT SOMEBODY SORT OF ROGUE GENES IN THERE SOMEWHERE.
YOU CAN COMPARE ME, THIS IS A WOMAN FROM THE BERBER POPULATION IN NORTH AFRICA.
A MUCH MORE INTERESTING GENOME. HERE WE SEE MOSTLY EUROPEAN ANCESTRY, I THINK
IT'S 86% BUT SOME SIGNIFICANT AFRICAN ANCESTRY, A LITTLE BIT OF ASIAN ANCESTRY AS ESTIMATED
BY THE MARKERS USED BY THIS COMPANY. THE IMPORTANT POINT HERE, THOUGH, IS THAT
SECTIONS OF THIS PERSON'S CHROMOSOME MIGHT BE OF EUROPEAN ORIGIN, THEY MIGHT BE OF AFRICAN
ORIGIN. BIOMEDICALLY SIGNIFICANT GENES IN THIS PERSON
MIGHT BE OF EUROPEAN ORIGIN, MIGHT BE OF AFRICAN ORIGIN.
ONCE AGAIN ANCESTRY GIVES US A MUCH MORE COMPLEX VIEW OF THIS PERSON'S GENETIC LEGACY THAN
DOES CATEGORY LIKE RACE. GOING BACK TO MY ANCESTRY, I ALSO DID GET
A REPORT BACK ON MY Y CHROMOSOME, THIS IS Y CHROMOSOME THAT IS PRETTY COMMON IN NORTHERN
EUROPEAN, NORTHERN EUROPE, I LEARNED THAT I SHARE IT WITH JIMMY BUFFET AND WARREN BUFFET.
HASN'T DONE ANYTHING FUR MY SINGING OR INVESTING BUT IT WAS INTERESTING FACTOID.
I DON'T HAVE GENGUS KHAN'S Y CHROMOSOME. I DON'T KNOW IF WE KNOW WHAT HIS REALLY WAS.
THIS IS HISTORICAL FROLICKING I THINK. IT IS INTERESTING TO DO THIS SORT OF RECREATIONAL
GENOMICS I ALSO GOT REPORT BACK ON MY MATERNAL HAPLO GROUP WHICH NOT SURPRISING IS ALSO COMMON
IN EUROPE. WHAT DID THESE KINDS OF FINDINGS IMPLY FOR
BIOMEDECIN? IF WE LOOK AT A LOT OF DNA POLYMORPHISMS WE
CAN LEARN SOMETHING ABOUT ANCESTRY AND POPULATION 'TIS OTHER REWITH IMPORTANT QUALIFICATIONS
THAT NOT EVERYONE FALLS IN TO GROUPS. AND THAT THERE ARE OF COURSE ASSUMPTIONS MADE
IN MAKING THESE INFERENCES. RESPONSES TO THERAPEUTIC DRUGS MAY INVOLVE
VARIATION IN FEW GENES AND ALSO GOING TO BE AFFECTED BY ENVIRONMENT.
WHAT THAT MEANS IS THAT THOSE GENETIC CLASSIFICATIONS DON'T NECESSARILY TELL US THAT MUCH ABOUT
BIOMED I CANNILY SIGNIFICANT PHENOTYPES. HERE IS A GREAT EXAMPLE.
WE TALKED EARLIER ABOUT THE AFFECTS OF ACE INHIBITORS IN AFRICAN AMERICANS VERSUS EUROPEAN
AMERICANS. THIS IS A METAANALYSIS PUBLISH ADD FEW YEARS
AGO LOOKING AT THE DECREASE IN BLOOD PRESSURE THAT OCCURRED AFTER ADMINISTRATION OF ACE
INHIBITORS IN THOUSANDS OF EUROPEAN HYPERTENSIVES AND AFRICAN AMERICAN HYPERTENSIVES WHAT WE
SEE IS THAT ON AVERAGE THERE IS ABOUT A FIVE MILLIMETER DIFFERENCE IN RESPONSE, THAT IS
AFRICAN AMERICANS ON AVERAGE DON'T RESPOND QUITE AS MUCH AS EUROPEAN AMERICANS.
TO ACE INHIBITORS IN TERMS OF LOWERING THEIR BLOOD PRESSURE.
BUT YOU CAN ALSO SEE THAT THERE'S A LOT OF OVERLAP BETWEEN THESE TWO CURVES.
A LOT OF AFRICAN AMERICANS WOULD ACTUALLY RESPOND BETTER THAN A LOT OF EUROPEAN AMERICANS
TO AN ACE INHIBITOR. ONCE AGAIN USING A CATEGORY LIKE RACE TO PREDICT
RESPONSE GIVES US SOME INFORMATION BUT IT CAN ALSO MISLEAD US.
HERE IS ANOTHER GOOD EXAMPLE. THE DRUG GEFITINIB, TREATS NON-SMALL CELL
LUNG CANCER. IT'S AN EGFR INHIBITOR.
IT IS EFFECTIVE AT LEAST FOR AWHILE IN IN ABOUT 10% OF EUROPEANS, ROUGHLY 30% OF ASIANS.
SO YOU MIGHT BE TEMPTED TO THINK, WELL WE COULD USE POPULATION AFFILIATION TO HELP PREDICT
WHO IS GOING TO RESPOND TO THIS DRUG. AFTER ALL THREEFOLD DIFFERENCE IN DIFFERENT
POPULATIONS. SOMATIC MUTATIONS IN EGFR ARE SEEN IN ABOUT
10% OF EUROPEANS WHILE 30% OF JAPANESE PATIENTS, WHAT'S REALLY INTERESTING IS THAT, 80% OF
THOSE WHO HAVE THESE EGFR MUTATIONS RESPOND TO GEFITINIB AND 10% WITHOUT THE MUTATION.
WE CAN SEE WE GET MUCH BETTER PREDICTOR OF RESPONSE TO THE DRUG THAN IF WE LOOK AT POPULATION
AFFILIATION. I'M GLAD TO SEE MY ANTI-VIRUS IS WORKING.
THAT LEADS US TO A THEME THAT YOU'VE HEARD ABOUT AND HEAR MORE ABOUT IN THIS SERIES,
TALK ABOUT PERSONALIZED MEDICINE THE NOTION THAT NOW THAT WE CAN LOOK AT INDIVIDUAL VARIATION
THAT IS MUCH MORE APPROPRIATE TARGET AND MUCH MORE APPROPRIATE MEANS OF DECIDING THERAPY,
ONCE WE HAVE THE INFORMATION, WITHIN WE CAN MAKE THE PREDICTION THAN USING BROAD CATEGORIES
LIKE RACE OR POPULATION AFFILIATION. WHAT I HAVE TOLD YOU ABOUT WE DO SEE CORRELATION
BETWEEN GEOGRAPHIC LOCATION AND GENETIC VARIATION BUT THAT VARIATION IF WE SAMPLE ENOUGH OF
IT WE START TO SEE ESSENTIALLY CONTINUOUS NON-INTERRUPTED VARIATION ACROSS.
I THINK THAT OUR TRADITIONAL CONCEPTS OF RACE MAY NOT BE ACTUALLY BIOLOGICALLY MEANINGLESS
THAT MIGHT BE AN OVER STATEMENT. BUT IT'S BIOLOGICALLY VERY IMPRECISE, IT IS
A BLUNT TOOL, CONCEPTS LIKE ANCESTRY LOOKED AT AT THE INDIVIDUAL LEVEL ARE CERTAINLY GOING
TO BE MORE INFORMATIVE. WE HOPE THAT PERSONALIZED MEDICINE, WHEN IT
BECOMES A REALITY, WILL BE MEDICALLY A LOT MORE USEFUL THAN CATEGORY LIKE ETHNICITIES
OR RACE. I THINK FINALLY, THIS IS POINT THAT CAN'T
BE EMPHASIZED ENOUGH, THERE IS NOTHING IN GENETICS THAT SUPPORTS RACIST THINKING, THINKING
THAT WITHIN GROUP IS IN SOME WAY SUPERIOR TO ANOTHER.
AND IN FACT I THINK A LOT OF EVIDENCE THAT CONTRADICTS THAT KIND OF THINKING BECAUSE
WE CAN WITH GENETIC DATA ASCERTAIN HOW SIMILAR WE ALL FOR ONE ANOTHER.
HOW MUCH VARIATION WE DO SHARE. I THINK ACTUALLY GENETICS IS AN IMPORTANT
TOOL THAT CAN HELP TO COMBAT RACIST THINKING. WHAT I WOULD LIKE TO DO NOW BECAUSE I THINK
90 MINUTES IS TOO LONG FOR HUMANS TO SIT DOWN IN ONE PLACE I'M GOING TO SHOW YOU A NICE
PRETTY PICTURE TAKEN FROM JUST A FEW MILES FROM MY HOUSE IN UTAH.
I'M GOING TO ASK TO YOU STAND UP FOR ABOUT A MINUTE OR SO AND JUST STRETCH.
WE'LL HAVE A LITTLE BREAK. WE'LL GO ON TO THE THIRD PART OF THE TALK.
>> OKAY, I THINK WE'LL GET STARTED AGAIN. HOPE YOU ENJOYED YOUR BREAK.
IN THE LAST PART OF MY TALK, WHAT I WOULD LIKE TO DISCUSS, YOU'LL BE DISCUSSING MORE
OF THIS AS THIS SERIES PROCEEDS, IS HOW OUR UNDERSTANDING OF POPULATION GENETICS AND EVOLUTIONARY
GENETICS HELPS US TO UNDERSTAND HAPLOTYPE DISTRIBUTIONS, THE CONTENTS AND HOW IT HELPS
US TO DESIGN MORE EFFECTIVE GENE MAPPING STUDIES. THIS IS REALLY A BRIDGE BETWEEN POPULATION
GENETICS AND EVOLUTIONARY GENETICS ON THE ONE HAND AND GENE MAPPING ON THE OTHER.
THE TWO HAVE BECOME I THINK REALLY INTER-TWINED OVER THE LAST DECADE OR SO.
SOMEBODY WITH INTEREST IN BOTH AREAS I'VE BEEN VERY GRATIFIED TO SEE MUTUAL INTEREST
IN BOTH POPULATION GENETICS AND GENE MAPPING AND LOCATION.
IF WE LOOK AT SNP FREQUENCIES ACROSS HUMAN POPULATIONS, WE FIND AT LEAST ROUGHLY THAT
A SNP WITH A MINOR ALLELE FREQUENCY GREATER THAN 1% OCCURS ABOUT ONE EVERY 300 BASE PAIRS
IN THE GENOME. THIS DEPENDS A LITTLE BIT ON POPULATION, BUT
ROUGHLY WE CAN SAY THAT THERE ARE AT LEAST TEN MILLION SNP IN THE GENOME WHERE THE MINOR
ALLELE FREQUENCY IS GREATER THAN 1%. THEY WOULD BE CONSIDERED UNDERATE ADDITIONAL
DEFINITION POLYMORPHISM. A COMMON SINGLE NUCLEOTIDE POLYMORPHISM, THAT
IS WITH THE MINOR ALLELE FREQUENCY GREATER THAN 5% WE HAVE ABOUT FIVE MILLION OR SO OF
THOSE. AT LEAST ROUGHLY.
THAT MEANS THAT AT EVEN RELATIVELY MODEST COST, LET'S SAY A TENTH OF A CENT PER SNP
IF WE HAD -- WANTED TO GENOTYPE ALL FIVE MILLION OF THOSE VARIANTS, IT WOULD COST $5,000 PER
PERSON. MAYBE TWO OR THREE THOUSAND BUT STILL A LOT
OF MONEY PER SAMPLE. IF WE WANT TO DO CASE CONTROL ASSOCIATION
STUDY COMPARING A THOUSAND CASES AND THOUSAND CONTROLS, THESE DAYS THIS IS PRETTY AFTERNOON
MINIMUM SAMPLE SIZE, IT WOULD COST $15 MILLION TO GENOTIME ALL FIVE MILLION OF THOSE SNPS.
SO, THIS WAS A REAL PROBLEM. DID WE REALLY NEED TO TEST ALL OF THESE SNP
IN ORDER TO ASSESS VARIATION IN DOING A CASE CONTROL STUDY?
WOULD THE SNP ASSOCIATION TEST REVEAL ANYTHING. I'LL START WITH COUPLE OF VERY SIMPLE DEFINITIONS
BECAUSE I KNOW WE HAVE A DIVERSE AUDIENCE HERE.
FIRST WE'LL DEFINE A HAPLOTYPE AS THE DNA SEQUENCE FOUND ON ONE MEMBER OF THE CHROMOSOME
PAIR. IN THIS WE SEE TWO SETS OF ALLELES, SO FORTH.
WE TRANSMIT THOSE HAPLOTYPES TO OUR OFFSPRING. NOW, AS YOU KNOW DURING MEIOSIS, CROSSOVERS
CAN OCCUR BETWEEN HOMOLOGOUS PAIRS OF CHROMOSOMES LIKE THIS, RESULTING IN RECOMBINATION OF ALLELES,
NOW THIS PARENT TRANSMITS THE NEW HAPLOTYPE. A HAPLOTYPE WITH A NEW COMBINATION OF ALLELES
TO HIS OFFSPRING. THESE VERY FUND FUND MENTAL CROSS OVER ALLOW
US TO ESTABLISH THE RELATIVE DIFFERENCES BETWEEN LOCI IN THE HUMAN GENOME.
WE CAN ASK HOW OFTEN DO THEY OCCUR? OVER TIME THEN WE EXPECT MORE CROSSOVERS BETWEEN
LOCI THAT ARE LOCATED FURTHER APART. A AND B ARE FURTHER APART.
WE OBSERVE MORE CROSSOVERS BETWEEN THAT PAIR OF LOCI THAN BETWEEN B AND C.
WHAT THAT MEANS IS THAT, AFTER MANY GENERATIONS WE'RE GOING TO FIND ALLELES B AND C, THAT
IS BIG B AND C, TOGETHER ON THE SAME COPY OF THE CHROMOSOME MORE OFTEN THAN WE WILL
FIND BIG A AND BIG B. BECAUSE THESE RECOMBINED TO GET LITTLE BIG
A, WITH LITTLE B. AND EVENTUALLY WE TEND TO REASSORT THESE ALLELES.
WHAT WE'RE SEEING IS THAT THERE IS MORE LINKAGE DISEQUILIBRIUM BETWEEN THESE PAIR OF LOCI
THAN BETWEEN THIS PAIR OF LOCI. THIS PAIR OF LOCI ARE FOUND TOGETHER MORE
FREQUENTLY THAN WE EXPECT BY CHANCE. THAT WHAT WE MEAN BY LINKAGE DISEQUILIBRIUM.
HERE IS A LITTLE DIAGRAM, AGAIN ILLUSTRATING THE IDEA.
THE LINKAGE, NONE RANDOM ASSOCIATION OF ALLELES AT LINKED LOCI.
AT EQUILIBRIUM. WE WOULD EXPECT TO SEE EVERY POSSIBLE COMBINATION
BIG A AND BIG B. LITTLE A AND LITTLE B AS WE LOOK AT COP PIECE
OF CHROMOSOMES IN OUR POPULATION. WE CAN ASSESS THE FREQUENCIES OF THOSE ALLELES,
BIG A AND LITTLE B. BY AN UNDER EQUILIBRIUM UNDER LINKAGE EQUILIBRIUM,
YOU HAVE BIG A AND B TOGETHER THAT SHOULD EQUAL THE FREQUENCIES OF THOSE ALLELES IN
THE POPULATION. THAT IS 60% "TIMES" 40%.
AND 06% TIMES 30% OR 18% OF THE TIME. SO FORTH.
IN OTHER WORDS, THESE LOCI, THEIR ALLELES ARE INDEPENDENT OF EACH OTHER THEY'RE AT EQUILIBRIUM.
WE WE CAN MULTIPLY THEIR RESPECTIVE FREQUENCIES TO GET HAPLOTYPE FREQUENCY F. WE SEE A SUBSTANTIAL
DEVIATION FROM THAT AS WE SEE IN THIS DIAGRAM WHERE BIG A AND BIG B ARE FOUND TOGETHER ON
THE SAME COPY OF A CHROMOSOME ON THE SAME HAPLOTYPE MORE FREQUENTLY THAN WE EXPECT BY
CHANCE, BIG A -- LITTLE A AND B ARE ALSO FOUND MORE FREQUENTLY THAN WE EXPECT BY CHANCE:
THEN WE HAVE LINKAGE DISEQUILIBRIUM. THERE HAVEN'T BEEN ENOUGH RECOMBINATIONS TO
RANDOMLY REASSORT THESE ALLELES IN OUR POPULATION. WHAT THAT SUGGESTS IS THAT A AND B ARE LIKELY
FAIRLY CLOSE TOGETHER. IMAGE HOW LINKAGE DISEQUILIBRIUM WOULD ARISE.
QUICK EQUILIBRIUM QUICK FOR A FEW GENERATIONS EVERY TIME WE SEE THE CF MUTATION WE'RE GOING
TO SEE THESE ALLELES NEARBY. THESE ALLELES, ALTERNATIVE SHOWN HERE ARE
NOT ASSOCIATED WITH THE MUTATION. THEY'RE GOING TO BREAK UP THE ASSOCIATIONS.
ON THIS CHROMOSOME COPY IN THE PRESENT DAY POPULATION, WE SEE OUR CF MUTATION CO-OCCURRING
NOT WITH BIG B BUT WITH LITTLE D. BUT WE STILL TEND TO SEE ASSOCIATIONS BETWEEN
OUR MUTATIONS AND SNPS THAT ARE VERY NEARBY. SO EVACUEE STILL SEE UPPER CASE G -- WE --
WHEN WE SEE OUR DISEASE CAUSING MUTATION BECAUSE IT'S VERY CLOSE.
SO CLOSE THAT REBY MAKES STILL HASN'T HAD TIME -- RECOMBINATION TO REASSORT OUR MUTATION
WITH THE ALTERNATIVE ALLELE, LITTLE G. THIS IS WHAT WE MEAN BY LINKAGE DISEQUILIBRIUM
TO PINPOINT THE CYSTIC FIBROSIS GENE BACK IN THE LATE 1980S.
IN FAMILIES WITH LINKAGE DISEQUILIBRIUM THIS IS SOMETHING THAT WE CAN ESTIMATE IN POPULATION.
WE HAVE OF COURSE MICROARRAY TECHNOLOGY NOW THAT ALLOWS US TO LOOK AT VERY DENSE ARRAYS
OF SNPS TO DO OUR GENOTYPING. THE REAL ADVANTAGE OF LINKAGE DISEQUILIBRIUM
IS THAT IT IN ESSENCE INCORPORATES MANY PAST GENERATIONS OF RECOMBINATION.
EVERY RECOMBINATION THAT HAS OCCURRED SINCE THE MUTATION TOOK PLACE.
I'D LIKE TO SHOW THIS IS AS CONTRAST. HERE IS A THREE GENERATION OF FAMILIES, COUNSELED
RECOMBINATIONS TO ESTIMATE THE DISTANCE BETWEEN LOCI.
WE'RE LIMITED TO THE NUMBER OF GENERATIONS THAT WE CAN ACTUALLY COLLECT.
BUT WITH LINKAGE DISEQUILIBRIUM WHAT WE'RE EFFECTIVELY DOING IS GOES GO BACK TO THE COMMON
ANCESTOR IN WHOM THIS DISEASE FIRST OCCURRED. OUR HOME IN THESE FAMILIES THEY ALL SHARE
THE SAME DISEASE CAUSING MUTATION DESCENDED FROM THE COMMON ANCESTOR WITH LINKAGE DISEQUILIBRIUM
WE'RE INCORPORATING THE EFFECTS OF THE RECOMBINATIONS OCCURRED OVER MANY GENERATIONS.
SINCE THE MUTATION FIRST OCCURRED. WHAT THAT MEANS IS THAT LINKAGE DISEQUILIBRIUM
CAN ALLOW US TO MORE FINALLY LOCALIZE THE DISEASE CAUSING MUTATION BECAUSE WE HAVE LOT
MORE RECOMBINATIONS EFFECTIVELY TO LOOK AT. BECAUSE POPULATIONS WITH REGARD TO ANY SPECIFIC
MUTATION ARE EE ISN'T SYSTEMLY ONE BIG PEDIGREE. ONE BY KATE PEDIGREE CHASING BACK -- THIS
LINKAGE DISEQUILIBRIUM HAS INTERESTING HISTORY, WHEN I FIRST BECAME INTERESTED IN IT, I HAVE
TO ADMIT IT WAS A LONG TIME AGO BACK ABOUT 1982 A GUY NAMED DAVID BARKER WHO WAS POST
DOC OF RAY WHITE CAME TO MY OFFICE HAD FOUR BRAND NEW RFLPS.
BACK IN THOSE DAYS FOUR NEW POLYMORPHISMS WAS A BIG DEAL HE GOT THE LEAD ARTICLE IN
THE AMERICAN JOURNAL OF HUMAN GENETICS THAT ISSUE.
WE WERE LOOKING AT LINKING A DISEQUILIBRIUM PATTERNS THAT'S WHEN I GOT INTERESTED IN THAT
PHENOMENON OF LINKAGE DISEQUILIBRIUM. I HAS INTERESTING PROPERTIES IN POPULATION
GENETICS. BUT IF YOU LOOK BACK AT THAT TIME, ONLY ABOUT
20 ARTICLES PER YEAR WERE PUBLISHED ON LINKAGE DISEQUILIBRIUM.
COULD READ A PAPER KNOW EVERYTHING THERE WAS ABUT THIS TOPIC.
NOW WE'RE CLOSE TO 2,000 PAPERS. YOU'D HAVE TO READ 30 OR 40 PAPERS A WEEK
TO KEEP UP THAT WITH LITERATURE. NOT THAT ALL ARE WORTH READING.
THIS INDICATES HOW MUCH INTEREST THERE IS IS IN THE TOPIC NOW OF LINKAGE DISEQUILIBRIUM.
RELATIVE TO SAY 25 YEARS AGO. THE QUESTION IS, IS THERE A SIMPLE, UNIFORM
RELATIONSHIP BETWEEN INTER-LOCUS PHYSICAL DISTANCE IN THE GENOME AND LINKAGE DISEQUILIBRIUM.
IN OTHER WORDSF WE KNOW THE AMOUNT OF LINKAGE DISEQUILIBRIUM, THE AMOUNT OF NONRANDOM ASSOCIATION
BETWEEN TWO LOCI, HOW WELL CAN WE PREDICT HOW FAR APART THEY ACTUALLY ARE.
THIS IS THE RELATIONSHIP THAT WE WOULD EXPECT THAT HAS DISTANCE BETWEEN LOCI INCREASES,
LINKAGE DISEQUILIBRIUM DECREASES. IT GOES EVENTUALLY TO ZERO.
IT'S OFTEN MEASURED WITH R, CORRELATION COEFFICIENT SO THAT IN COMPLETE DISEQUILIBRIUM, THAT IS
WHEN WE CAN PERFECTLY PREDICT THE ALLELE AT ONE LOCUS IF WE KNOW THE ALLELE STATUS AT
NEARBY LOCUS THEN RAILROAD IS EQUAL TO ONE. IF THERE'S NO RELATIONSHIP UNDER EQUILIBRIUM
R IS EQUAL TO ZERO NO CORRELATION. THIS IS THE RELATIONSHIP THAT WE EXPECT.
SOME YEARS AGO WE LOOKED AT A NUMBER OF RFLPS NEAR THE GENE.
WE WERE INTERESTED IN THE DISTANCE, EACH OF THESE POINTS REPRESENTS A PAIR OF POLYMORPHISMS
AND THE QUESTION WAS, DOES DISEQUILIBRIUM BETWEEN PAIRS OF POLYMORPHISMS DECREASE AS
WE LOOK AT POLYMORPHISMS THAT ARE FURTHER APART.
HERE WE LOOKED ACROSS ABOUT 600KB. INDEED WE DID FIND SIGNIFICANT NEGATIVE RELATIONSHIP
BETWEEN DISEQUILIBRIUM AND DISTANCE BETWEEN THESE POLYMORPHIC MARKERS.
THAT WAS EARLY INDICATION THAT LINKAGE DISEQUILIBRIUM POTENTIALLY COULD BE USED TO FINALLY LOCALIZE
GENES ON CHROMOSOMES. HERE IS ANOTHER EXAMPLE OF THIS PLOT WHICH
IVORY DUESED TO SMALL SIZE HAS SERIES OF POINTS HERE, THEN SERIES OF POINTS THAT DOESN'T CORRESPOND
TO OUR RELATIONSHIP AT ALL. IT'S NOT THE DECREASE, MONOTONIC DECREASE
IN DISEQUILIBRIUM WITH DISTANCE THAT WE WOULD EXPECT.
THIS WAS AN ANALYSIS WE DID IN THE NEUROFIBROMITOSIS TYPE ONE REGION.
WHAT WE FOUND FOR ALL OF THESE MARKERS, ALL PAIRS WERE IN SUBSTANTIAL DISEQUILIBRIUM WITH
AN R FALL VIEW GREATER THAN .82 BUT THERE WAS ANOTHER ONE JUST 68KB AWAY FROM ITS NEAREST
NEIGHBOR WHERE THERE WAS NO DISEQUILIBRIUM BETWEEN IT AND ALL OF THE OTHER MARKERS.
WE HAD LOT OF HYPOTHESES AT THE TIME TO ACCOUNT FOR THIS.
IT WAS A GC-RICH REGION, RECOMBINATION IS SOMEWHAT ASSOCIATED WITH GC CONTENT.
BUT WHAT ULTIMATELY WE LEARNED FROM THE HAPMAP DATA IS THAT THERE IS A RECOMBINATION HOT
SPOT RIGHT IN THIS AREA. SO THE RECOMBINATION HOT SPOT LOCATED RIGHT
HERE EXPLAINS WHY THIS POLYMORPHISM IS NOT IN EQUILIBRIUM -- NOT IN DISEQUILIBRIUM, EVEN
WITH ONE THAT IS ONLY 70KB AWAY. WE DON'T ALWAYS SEE THE UNIFORM RELATIONSHIP
THAT WE MIGHT EXPECT BETWEEN DISTANCE, THAT IS PHYSICAL DISTANCE BETWEEN POLYMORPHISMS
AND LINKAGE DISEQUILIBRIUM BETWEEN THEM. BECAUSE AMONG OTHER THINGS WE HAVE HOT SPOTS
THROUGHOUT THE HUMAN GENOME. THERE ARE NUMBER OF FACTORS THAT CAN AFFECT
LINKAGE DISEQUILIBRIUM PATTERNS. CHROMOSOME LOCATION, RECOMBINATION MORE COMMON
WITH TELOMERES THAN ELSEWHERE. DNA SEQUENCE PATTERNS, GC CONTENT WE FOUND
THAT ALU ELEMENTS INFLUENCE RECOMBINATION AND INCREASE RECOMBINATION BY A FEW PERCENT.
THERE ARE A LOT OF ALU ELEMENTS THROUGHOUT THE GENOME.
THERE ARE RECOMBINATION HOT SPOTS EVERY 50 TO 100KB, WHAT I THINK IS ESPECIALLY INTERESTING
IS THAT EVOLUTIONARY FACTORS INFLUENCE PATTERNS OF LINKAGE DISEQUILIBRIUM IN THE HUMAN GENOME.
THINGS LIKE NATURAL SELECTION, GENE FLOW, GENE CONVERSION, GENETIC DRIFT.
ALL OF THE FACTORS THAT PEOPLE LIKE TO THINK ABOUT INFLUENCE PATTERNS OF LINKAGE DISEQUILIBRIUM
BECAUSE DISEQUILIBRIUM REFLECTS THE HISTORIES OF POPULATIONS.
THE FACTORS IN POPULATIONS THAT HAVE AFFECTED GENETIC VARIATION.
THERE ARE SOME INTERESTING IMPLICATIONS OF OUR POPULATION GENETIC STUDIES FOR DISEQUILIBRIUM
PATTERNS. WE'VE SEEN THAT THERE IS CONDITION VARIATION,
EVEN VARIATION WITHIN MAJOR CONTINENTS THAT IS GOING TO AFFECT STRATIFICATION PATTERNS
SHOULD BE TAKEN IN TO ACCOUNT WHEN WE'RE DESIGNING CASE CONTROL ASSOCIATION STUDIES.
THE FACT THAT THE AFRICAN POPULATIONS WERE FOUNDED FURTHER AGO IN TIME, IN OTHER WORDS,
THEY HAVE -- WE CAN SAY A GREATER AGE IMPLIES THAT WE SHOULD SEE LESS LINKAGE DISEQUILIBRIUM
IN THOSE POPULATIONS. THAT IS THERE HAS BEEN MORE TIME FOR RECOMBINATIONS
TO OCCUR IN THOSE POPULATIONS, WE'RE GOING TO SEE LINKAGE DISEQUILIBRIUM PERSISTING OVER
SHORTER DISTANCES BECAUSE OF MORE RECOMBINATIONS. WE'VE SEEN GREATER DIVERGENCE OF AFRICAN POPULATIONS,
WHAT THAT IMPLIES IS THAT WHAT WE SOMETIMES CALLED ADMIXTURE LINKAGE DISEQUILIBRIUM, REFLECTS
MIX TOURS OF AFRICAN AND NON-AFRICAN POPULATIONS WE DON'T HAVE TIME HERE TO TALK ABOUT AD MIXTURE
DISEQUILIBRIUM, BUT IT'S STARTING TO BE APPLIED WITH SOME LEVEL OF SUCCESS.
HERE IS WAY IN WHICH POPULATION GENETICISTS ARE UNDERSTANDING HAPPEN LAY TYPE STRUCTURE
AND GENE MAPPING. IF WE THINK OF POPULATIONS THAT WERE FOUNDED
A LONG TIME AGO THERE HAVE BEEN MANY GENERATIONS OR RECOMBINATIONS TO OCCUR AS WE SEE HERE.
THAT MEANS THAT WE'RE GOING TO SEE RELATIVELY SHORT GROUPS OF LAP LOW TYPES, OR HAPLOTYPE
BLOCK, IS THAT THEY'RE CALLED. A POPULATION THAT WAS FOUNDED RELATIVELY RECENTLY
EXAMPLE MIGHT BE POPULATION OF FINLAND, OF MOST OF WHICH WAS FOUNDED JUST COUPLE THOUSAND
YEARS AGO. THERE HASN'T BEEN AS MUCH TIME TO RECOMBINATIONS
TO OCCUR IN THOSE -- IN POPULATION LIKE THAT. SO WE HAVE FEWER HAPLOTYPES IN LARGER BLOCKS.
THERE'S MORE DISEQUILIBRIUM, LESS HAPLOTYPE DIVERSITY.
SO IF WE THINK ABOUT MUTATION, THAT MAY HAVE OCCURRED IN THAT POPULATION, COUPLE THOUSAND
YEARS AGO, IT'S GOING TO BE IN DISEQUILIBRIUM WITH A LARGE NUMBER OF SNPS.
HASN'T BEEN MUCH TIME FOR RECOMBINATION TO CAUSE THOSE TO DECAY.
IN CONTRAST MUTATION THAT OCCURRED IN AN AFRICAN POPULATION WILL HAVE HAD MORE TIME TO DURING
WHICH CAN REDUCE ASSOCIATION WITH NEARBY SNPS. WE FIND THAT MUTATION IN ASSOCIATION WITH
SMALLER NUMBER OF SNPS. IN OTHER WORDS WE'RE GOING TO NEED MORE SNPS
IN THIS POPULATION TO FIND ASSOCIATION THAN IN THIS POPULATION.
CONVERSELY IN THIS POPULATION, WE CAN MORE FINALLY MAP THE LOCATION OF A MUTATION BECAUSE
IT'S IN ASSOCIATION WITH JUST A FEW NEARBY SNPS.
SOME IMPORTANT ATTRIBUTES OF HISTORY THAT HELP TO INFORM US ABOUT THE DESIGN OF ASSOCIATION
STUDIES. IF WE LOOK AT SOME REAL DATA, THIS IS KIND
OF DISPLAY THAT WE GET FROM THE PROGRAM HAPLOVIEW. LET ME EXPLAIN WHAT WE'RE LOOKING AT HERE
BECAUSE WE SEE THESE ALL THE TIME IN THE ASSOCIATION STUDY LITERATURE.
THIS IS A MAP OF LINKAGE DISEQUILIBRIUM. EACH OF THESE LITTLE COLUMNS HERE REPRESENTS
A SNP. THEY ARE ARRAYED ACCORDING TO THEIR PHYSICAL
LOCATION ACROSS THE CHROMOSOME, AND THEN EACH OF THESE SQUARES LIKE THIS RED SQUARE HERE,
INDICATES THE LINKAGE DISEQUILIBRIUM BETWEEN A PAIR OF SNPS.
FOR THIS ADJACENT PAIR OF SNPS RIGHT HERE, WE HAVE RED, WE HAVE HIGH DISEQUILIBRIUM,
OR THIS PAIR, THAT IS THIS ONE AND THIS ONE, WE HAVE LITTLE DISEQUILIBRIUM.
AN ANALOGY WOULD BE THE MILEAGE CHARTS THAT SOME OF US HAVE USED WHERE WE CAN TAKE ANY
PAIR OF CITIES, LET'S SAY NEW YORK AND SAN FRANCISCO AND WE CAN SAY, WHAT'S THE DISTANCE
BETWEEN THEM. FOR A PAIR OF SNPS WHAT IS THE DISEQUILIBRIUM.
THERE'S A LOT MORE DISEQUILIBRIUM IN THIS EURASIAN SAMPLE THAN THE AFRICAN SAMPLE CONSISTENT
WE SEE SNIPS OCCURRING IN MUCH LARGER -- SNPS IN HAPLOTYPE BLOCKS IN THESE POPULATIONS
THAN IN THESE. THAT HAS IMPORTANT IMPLICATIONS FOR STUDY
DESIGN. I'VE SHOWED YOU EXAMPLES, NOW GENERAL ARE
THESE PATTERNS? IF WE LOOK ACROSS THE GENOME, WHAT KINDS OF
PATTERNS DO WE SEE? BACK ABOUT TEN YEARS AGO OUR KNOWLEDGE OF
THE HUMAN GENOME, OF LINKAGE DISEQUILIBRIUM ACROSS THE HUMAN GENOME WAS LOT LIKE THIS
MAP OF THE WORLD FROM 1544. WE REALLY DIDN'T KNOW MUCH ABOUT PATTERNS
OF DISEQUILIBRIUM OR HAPLOTYPE STRUCTURE ACROSS THE GENOME.
AND IF YOU LOOK AT THIS MAP WE HAVE FAIRLY GOOD REPRESENTATION OF EUROPE, SOME OF AFRICA
AND ASIA, YOU SEE NORTH AMERICA IS COMPLETELY ABSENT IN 1544.
THAT'S HOW OUR KNOWLEDGE OF HAPLOTYPE STRUCTURE ACROSS THE GENOME WAS ROUGHLY 10 OR 12 YEARS
AGO. THAT'S WHAT LED TO THE HAPMAP PROJECT.
I WANT TO MENTION THIS YOU'LL HEAR MORE ABOUT IT OTHER LECTURES AS WELL.
THE ORIGINAL IDEA WAS TO LOOK AT LARGE COLLECTION OF SNPS, 6700,000 EVENTUALLY WENT TO A MILLION
THEN MORE AFTER THAT. IN INDIVIDUALS FROM THREE MAJOR POPULATIONS.
906 THEM IN 30TRIOSER FROM THE UTAH CEPH COLLECTION. THIS REPRESENTED NORTHERN EUROPE.
90 YORUBAN AND 90 EAST ASIAN INDIVIDUALS. LOOK AT PATTERN OF LINKAGE DISEQUILIBRIUM
IN THESE DIFFERENT POPULATIONS AND TO LOOK AT HAPLOTYPE STRUCTURE TO SEE TO WHAT EXTENT
THESE VARIED AMONG POPULATIONS AND ACROSS THE GENOME.
THERE WERE SOME INTERESTING ISSUES THAT CAME UP IN THE EARLY DISCUSSIONS OF THE HAPMAP.
I WAS LUCKY ENOUGH TO BE PART OF THOSE DISCUSSIONS, ONE OF THE ISSUES WAS HOW BEST TO SAMPLE HUMAN
DIVERSITY IF YOU CAN ONLY SAMPLE FEW POPULATION. DECISION WAS TO TRY TO LOOK AT FAIRLY BROAD
SAMPLING BUT BY NO MEANS COMPLETE SAMPLING OF HUMAN DIVERSITY.
OF COURSE SAMPLE SIZE ISSUES, ISSUES INVOLVING SNP ASCERTAINMENT AND DENSITY THEN ALSO NUMBER
OF ETHICAL, LEGAL, SOCIAL ISSUES, THINGS LIKE INFORMED CONSENT.
EVEN SOME DISCUSSION OF WHETHER WE SHOULD NAME THE POPULATIONS OR NOT OR WHETHER THE
THREE POPULATIONS SHOULD NOT BE IDENTIFIED BECAUSE OF CONCERNS ABOUT POTENTIAL STIGMATIZATION.
THE POPULATION GENETICISTS FELT BECAUSE WE KNOW POPULATION HISTORY AFFECTS HOP LOW TYPE
STRUCTURE AND DISGIBB WE DON'T NAME THE -- WE DON'T KNOW THEIR HISTORY THAT WOULD BE
SEVERE LIABILITY. FOR THAT REASON WE DECIDED TO NAME THE POPULATION
AND I THINK THAT IS ADDED A LOT OF USEFULNESS IN INFORMATION TO THE HAPMAP SAMPLES.
SUBSEQUENT TO THAT I THINK OUR MAP OF THE WORLD IMPROVED.
YOU CAN SEE CALIFORNIA FOR SOME REASON STILL MISSING FROM THIS MAP.
BUT BY AND LARGE OUR KNOWLEDGE OF THE HUMAN GENOME IMPROVED -- OUR KNOWLEDGE OF DISEQUILIBRIUM
IN THE GENOME IMPROVED A GREAT DEAL. THERE HAVE BEEN A NUMBER OF INTERESTING APPLICATIONS
OF THE HAPMAP. FIRST OF ALL UNDERSTANDING WORLDWIDE GENOME
WIDE PATTERNS OF HAPLOTYPE DIVERSITY, DETECTING RECOMBINATION HOT SPOTS THROUGHOUT THE GENOME,
DETECTION OF GENES THAT HAVE EXPERIENCED NATURAL SELECTION THEN OF COURSE DETECTION OF DISEASE
CAUSING MUTATIONS. HERE IS AN EXAMPLE LOOKING AT THE DECAY OF
DISEQUILIBRIUM ACROSS GENOMIC REGIONS, IN THE HAPMAP POPULATION, THE ASIAN, EUROPEAN,
AFRICAN POPULATIONS, YOU CAN SEE THAT AS WE WOULD EXPECT WITH MORE RECOMBINATIONS DISEQUILIBRIUM
DECAYS MORE QUICKLY WITH PHYSICAL DISTANCE IN THE AFRICAN POPULATION.
IN THE YOURURBA,N AND MORE RECENTLY FOUNDED WE SEE THAT DISEQUILIBRIUM DOESN'T DECAY QUITE
AS RAPIDLY. AGAIN MORE RECENT HISTORY, FEWER RECOMBINATIONS,
MORE LINKAGE DISEQUILIBRIUM. WOULD GET PICTURES WITH THESE DATA.
ONE OF THE REALLY IMPORTANT CONSEQUENCES OF HAPMAP IS THAT WE'VE LEARNED THAT BECAUSE
OF THE PATTERN OF DISEQUILIBRIUM ACROSS THE GENOME A LOT OF SNPS ARE EFFECTIVELY REDUNDANT.
IF WE KNOW THAT THIS PERSON HAS A C AT THIS POSITION, THEY HAVE T AT ANOTHER POSITION,
AN A AT ANOTHER POSITION, BECAUSE OF LINKAGE DISEQUILIBRIUM.
WHERE AS PERSON B HERE HAS AN A AT THIS POSITION, G HERE, AND A C HERE, WHAT THAT TELLS US IS
THAT WE ONLY NEED TO TYPE THIS ONE IN ORDER TO KNOW THE GENOTYPES OF THESE.
IN OTHER WORDS, WE DON'T HAVE TO TYPE ALL FIVE MILLION COMMON SNPS.
WE CAN TYPE A SUBSET OF THEM WHAT WE CALL TAGGING SNPS AND GET PRETTY GOOD PICTURE OF
THE DIVERSITY ACROSS THE GENOME BY LOOKING AT THAT SUBSET OF VARIATION IS THAT IN ITSELF
IS A HUGE SAVING OF MONEY. THE TACT THAT WE CAN TYPE MAYBE A MILLION
SNPS IN NON-AFRICAN POPULATIONS AND ESSENTIALLY GET THE HAPLOTYPE DIVERSITY ACROSS THE GENOME
INSTEAD OF TYPING ALL FIVE MILLION IS A HUGE SAVINGS.
WE FIND NUMBER OF STUDIES LOOKED AT THE PORTABILITY OF THE HAPMAP TAGGING SNPS ACROSS POPULATIONS.
WE FIND THAT IN GENERAL THEY ARE PRETTY PORTABLE. THAT IS YOU CAN INFER PATTERNS OF DISEQUILIBRIUM
FROM ONE MAJOR POPULATION WITHIN A CONTINENT TO ANOTHER AND MOST OF THE TIME GET IT RIGHT.
AND FINDING HOT SPOTS WHERE DISEQUILIBRIUM SUDDENLY DECLINES.
WE DEFINE A REBY NATION HOT SPOT WHERE RECOMBINATION IS ELEVATED TENFOLD.
IT'S BEEN QUITE INTERESTING TO DISCOVER THAT THERE ARE TENS OF THOUSANDS OF HOT SPOTS IN
THE HUMAN GENOME. ROUGHLY ONE EVERY 50 TO 100KB.
WE RECENTLY LOOKED AT FAMILY, TWO PARENTS TWO, OFFSPRING LOOKED THEIR WHOLE GENOME SEQUENCE
FOUND 155 RECOMBINATIONS, 92 OF THEM WERE IN RECOMBINATION HOT SPOTS.
IN GENERAL THE DATA TELLS US THAT MOST CROSSOVERS AT LEAST 60% OCCUR IN ONLY ABOUT 10% OF THE
GENOME. HOT SPOTS REALLY ARE SIGNIFICANT IN TERMS
OF ACCOUNTING FOR MOST CROSSOVERS. ANOTHER REALLY INTERESTING FINDING FROM THESE
STUDIES OF RECOMBINATION IS THAT THEY'RE NOT AT ALL CONGRUENT IN HUMAN AND CHIMP.
EVEN THOUGH OUR DNA SEQUENCE IS 99% THE SAME, OUR HOT SPOTS ARE VERY, VERY DIFFERENT.
SUGGESTING THAT THESE EVOLVE VERY RAPIDLY, THEY MAY NOT BE SEQUENCE DEPENDENT THEY MAY
INVOLVE EPIGENETIC MECHANISMS. SO ALL KINDS OF INTERESTING QUESTIONS THAT
CAN BE ADDRESSED WITH DATA SUCH AS THOSE OF THE HAPMAP.
, WE CAN DETECT NATURAL SELECTION IN THE GENOME. THIS SLIDE SKETCHES OUT HOW WE DO THAT.
IMAGINE THAT A VARIANT OF THE INTEREST HAS OCCURRED, AND AS WE SAW IT OCCURS ON A SPECIFIC
CHROMOSOME BACKGROUND SO WE WILL SEE IT AT FIRST IN ASSOCIATION WITH NEARBY SNPS.
BUT OF COURSE WHEN IT FIRST OCCURS IT'S ALLELE FREQUENCY OVER HERE IS VERY LOW.
IF IT'S A NEUTRAL VARIANT IT MAY RISE IN FREQUENCY THROUGH TIME AS A RESULT OF GENETIC DRIFT.
BUT THAT INCREASES IN FREQUENCY IS GOING TO BE VERY SLOW.
WHAT HAPPENS AS THIS VARIANT, THE RED STAR, INCREASES IN FREQUENCY THROUGH TIME IS THAT
BECAUSE OF RECOMBINATION IT IS ASSOCIATED WITH FEWER AND FEWER NEARBY SNPS THROUGH TIME.
WE'RE GOING TO SEE VERY LITTLE DISEQUILIBRIUM BETWEEN THIS VARIANT AND LET'S SAY THIS SNP,
ONCE THE VARIANT GETS TO LET'S SAY 10% IN FREQUENCY.
BUT IF IT'S UNDER SELECTION, IF THERE HAS BEEN RECENT POSITIVE SELECTION FOR THAT VARIANT,
LET'S SAY CONFER SOME SORT OF ADAPTIVE ADVANTAGE, IT WILL RISE QUICKLY TO HIGH FREQUENCY, LET'S
SAY 10 OR 12%. AND BECAUSE OF SELECTION, BECAUSE SELECTION
HAS CAUSED IT TO RISE IN FREQUENCY VERY QUICKLY, IT WILL STILL BE IN DISEQUILIBRIUM WITH MANY
NEARBY SNPS. WE'LL HAVE VERY LONG RANGE OF LINKAGE DISEQUILIBRIUM
AROUND THAT VARIANT. WE'LL SEE THAT WHEN WE LOOK AT GENOMIC DATA
WE'LL SEE A REGION IN WHICH THERE IS HIGH DISEQUILIBRIUM OVER UNEXPECTEDLY LARGE DISTANCE.
THIS IS A SIGNATURE OF STRONG POSITIVE SELECTION ON THIS VARIANT.
THAT IS THAT THE VARIANT HAS RISEN TO HIGH FREQUENCY AND IS IN LARGE LINKAGE DISEQUILIBRIUM
BLOCK. THIS APPROACH HAS BEEN USED TO DETECT NATURAL
SELECTION INVOLVING A NUMBER OF PHENOTYPES. MALARIA RESISTANT, HEMOCHROMATOSIS, LACK TAKES
PERSISTENT, SKIN PIGMENTATION, SO FORTH. ANOTHER INTERESTING APPLICATION OF THESE DATA
BINDING REGIONS THAT HAVE BEEN STRONGLY AFFECT BY POSITIVE SELECTION IN HUMAN POPULATION.
HAS HAD SOME REAL SUCCESSES IN LOCALIZING SINGLE GENE DISORDERS.
THAT IS WHERE THEY WERE LOCI WERE FIRST MAPPED ROUGHLY BY USING LINKAGE ANALYSIS THEN DISEASE
CAUSING GENE WAS FOUND USING LINKAGE DISEQUILIBRIUM ANALYSIS.
TO PINPOINT THE ACTION GENE. MY DISPLAY HAS JUST FROZEN.
THESE KINDS OF STUDIES ARE VERY SUCCESSFUL IF WE -- IF MOST CASES OF THE DISEASE ARE
CAUSED BY SINGLE MUTATION. THAT MAKES SENSE.
IF THIS MUTATION IS ONLY ONE OR THE PRINCIPLE ONE THAT CAUSES DISEASE, THEN WE'RE GOING
TO BE ABLE TO EASILY DETECT 'SOAKS S QUAKES EVER DISEASE PHENOTYPE AND NEARBY SNPS.
IMAGINE IF WE HAVE MULTIPLE DISEASE CAUSING MUTATIONS.
THEN SOMETIMES WE'RE GOING TO SEE THE DISEASE WHEN WE SEE ONE GENOTYPE OR OTHER, WHEN THERE
ARE MULTIPLE DISEASE CAUSING MUTATIONS, WHEN THERE IS SUBSTANTIAL ALLELIC HETEROGENEITY
THAT PRESENTS REAL CHALLENGES IN DOING CASE CONTROL ASSOCIATION STUDIES.
SO, ONE OF OUR ISSUES IS HOW CAN WE REDUCE THAT HETEROGENEITY AND ENHANCE THE GENETIC
SIGNAL. WELL, CLEARLY, CONSISTENT TRAIT DEFINITION,
USE OF INTERMEDIATE PHENOTYPES WHO HELP TO DECREASE HETEROGENEITY.
WE CAN IDENTIFY SUBTYPES, THOSE WITH EARLY ONSET, SEVERE EXPRESSION, THIS IS WHERE CLINICIANS
CAN BE ESPECIALLY HELPFUL BECAUSE TYPICALLY CLINICIANS UNDERSTAND THOSE SUBTYPES AND CAN
INFORM GENETICIST AS TO WHICH GROUP OF CASES SHOULD USED IN AN OWE SAYS QUAKES STUDY.
USE OUR KNOWLEDGE OF EVOLUTIONARY HISTORY. TO DEFINE POPULATION IN VERY STRICT AND NARROW
FASHION SO THAT WE HAVE AS UNIFORM AN EVOLUTIONARY HISTORY AS POSSIBLE.
THERE MAY BE SITUATIONS IN WHICH POPULATION ISLETS WILL BE SPECIAL UTILITY.
SO THE BOTTOM LINE IS SOME OF YOU HAVE SEEN THESE DISPLAYS BEFORE WE CAN NOW POINT TO
QUITE A FEW GENOME WIDE ASSOCIATION STUDIES THAT HAVE BEEN SUCCESSFUL IN UNCOVERING VARIANTS
FOR COMMON COMPLEX DISEASE. THERE'S STILL A LOT LEFT TO BE DISCOVERED.
BECAUSE I THINK INTELLIGENT STUDY DESIGN, MUCH OF IT INFORMED BY OUR KNOWLEDGE OF POPULATION
GENETICS, THESE KINDS OF STUDIES HAVE BEEN MUCH, MUCH MORE SUCCESSFUL OVER THE LAST COUPLE
OF YEARS THAN PREVIOUSLY. THIS IS SOMETHING ELSE THAT YOU WILL HEAR
ABOUT, I THINK KAREN MULKEY WILL TALK ABOUT THIS LATER IN THIS SERIES.
SO, TO SUMMARIZE, WHAT I'VE TOLD YOU THIS MORNING, WE SEE THAT GENETIC VARIATION, WE
LOOK AT SNP MICROARRAYS ARE LOOKING AT WHOLE GENOME SEQUENCE, IT DOES CONTAIN USEFUL INFORMATION
ABOUT OUR POPULATION HISTORY, OUR ANCESTRY. I THINK THAT OUR STUDIES OF GENETIC VARIATION
GIVES US MORE INFORMED, MORE NUANCED VIEW OF THE CONCEPT OF RACE AND TELL US MUCH MORE
ABOUT MEDICAL RELEVANCE THAN IF WE USE THESE BROAD CATEGORIES LIKE POPULATION AFFILIATION
OR RACE, AND POPULATION GENETIC ANALYSIS ESPECIALLY IN THE CONTEXT OF LINKING A DISEQUILIBRIUM
HAS PLAYED A CENTRAL ROLE IN UNDERSTANDING LINKAGE DISEQUILIBRIUM AND HOW IT IS 'PLOWED
TO MAPPING AND LOCALIZING DISEASE CAUSING MEANS.
FINALLY I HOPE YOU'VE GOTTEN SOME SENSE OF SOMETHING THAT NOT EVERYONE APPRECIATES, POPULATION
GENETICS CAN BE FUN. IT CAN TELL US INTERESTING THINGS, FUN THINGS
ABOUT OURSELVES, OUR POPULATIONS, AND EVEN ABOUT OUR PHENOTYPES IN GENERAL.
FINALLY I WANT TO ACKNOWLEDGE A NUMBER OF MY COLLEAGUES AT THE UNIVERSITY OF UTAH.
PEOPLE IN MY LAB AND OTHERS WHO HAVE CONTRIBUTED TO THE WORK I'VE TOLD YOU ABOUT.
MOBILE ELEMENT WORK
THAT I TOUCHED ON JUST A LITTLE BIT I'VE DONE IN COLLABORATION OVER MANY YEARS NOW WITH
MY COLLEAGUE AT LS, MARK BATZER. SOME WERE GATHERED BY THE MOLECULAR GYNECOLOGY
FOUNDATION. I WANT TO THANK ALL OF THESE PEOPLE FOR THEIR
CONTRIBUTIONS TO OUR RESEARCH I'D LIKE TO THANK ALL OF YOU FOR YOUR ATTENTION.
[APPLAUSE] I THINK WE HAVE A COUPLE OF MINUTES FOR QUESTIONS.
I'M JUST TOLD THAT USUALLY WE DON'T HAVE QUESTIONS. >> I'LL ASK ONE.
THIS FIELD OF ANALYZING LINKAGE DISEQUILIBRIUM, DOES IT WORK FOR VERY, VERY RARE MUTATIONS?
I WOULD CONCEIVE THAT IT WOULD HAVE TO BE PRETTY COMMON TO WORK.
>> IT COULD WORK FOR A RARE MUTATION THE PROBLEM IS THAT YOU NEED FAIRLY LARGE SAMPLE SIZE
AFFECTED INDIVIDUALS WHO ARE UNRELATED, AT LEAST NOT CLOSELY RELATED.
IF YOU GOT REALLY RARE MUTATION IT MIGHT BE VERY DIFFICULT TO GET LARGE ENOUGH SAMPLE
SAY 50 TO 100 CASES, THAT IS WHERE IT WOULD BE A CHALLENGE.
>> ALSO A LOT OF DISEASE CLASSES THAT ARE CAUSED BY MULTIPLE DIFFERENT TYPES OF MUTATIONS
LIKE CARDIOMYOPATHYS FOR ONE, IT WOULDN'T BE DIFFICULT TO USE LINKAGE DISEQUILIBRIUM
IN SUCH A CASE? >> YEAH.
IF THERE IS SUBSTANTIAL ALLELIC HETEROGENEITY. LOOK AT BRCA 1 WHERE THERE ARE HUNDREDS OF
DIFFERENT MUTATIONS, EACH OF THOSE OCCURS ON A DIFFERENT HAPLOTYPE BACKGROUND YOU'RE
NOT GOING TO SEE A CONSISTENT PATTERN ASSOCIATION. IF THERE'S STRONG ALLELIC HETEROGENEITY LINKAGE
DISEQUILIBRIUM BECOMES -- IT ISN'T ALWAYS VERY USEFUL.
>> THANKS. >> HAS ANYONE APPLIED PHYLOGENETICS TO SNPS?
>> YES. >> ARE THE RESULTS MEANINGFUL OR --
>> THE RESULTS THAT WE SEE, ARE YOU TALKING ABOUT PHYLOGENETICS ACROSS SPECIES?
OR WITHIN SPECIES? >> WITHIN SPECIES.
>> WE LOOK AT PATTERNS IN HUMANS, THEY'RE VERY CONSISTENT WITH WHAT WE'VE SEEN WITH
OTHER MARKERS, WHAT WE'VE SEEN IN WHOLE SEQUENCE, EVERY KIND OF POLYMORPHISM WE LOOK AT AUTOSOMAL
POLYMORPHISM GIVES US A PATTERN PHYLOGENETICALLY.