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