Download Molecular Genetics

Human Polymorphisms and
Genetic Anthropology
Prof. Connie J. Mulligan
Department of Anthropology
September 20, 2012
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Molecular genetics
• Genetics is the study of
heredity and variation of
organisms
– Classical, Mendelian genetics
traces the inheritance of
particular traits, or phenotypes
• Molecular genetics is the study
of heredity and variation using
molecules, such as DNA
Human karyotype
– Traces the inheritance of genes
or genetic variants
C. Mulligan, Copyright 2011
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A little terminology
• A gene is a piece of DNA
that is responsible for the
inheritance of a specific
characteristic
– eye color
– ability to process lactate
(drink milk)
• Gene  protein
Human chromosomes, Genetics, HartlC.and
Jones,
2000
Mulligan,
Copyright
2011
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A little terminology
• A gene is a piece of DNA
that is responsible for the
inheritance of a specific
characteristic
– eye color
– ability to process lactate
(drink milk)
• Gene  protein
– Coding = genes (~3%)
– Non-coding (~97%)
Human chromosomes, Genetics, Hartl C.
and
Jones,
2000
Mulligan,
Copyright
2011
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DNA = Deoxyribonucleic acid
• DNA is represented as
a sequence of letters
(nucleotide bases)
–
–
–
–
–
Adenosine = A
Guanine = G
Cytosine = C
Thymine = T
A-T and G-C pairs
TGTG
• DNA is a blueprint to
direct the synthesis of
proteins
Genetics, 2001, Hartl and Jones, Jones
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Genetic variants are changes in DNA
sequence between individuals
(A C-to-T variant is depicted in the DNA sequence below)
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Terminology
•
•
•
•
•
•
•
Genetic variant
Genetic marker
Mutation
Polymorphism
SNP (single nucleotide polymorphism)
Biallelic marker
All of these terms are used to refer to genetic
differences between individuals or populations
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A little more terminology
• Phenotype
– Physical characteristics of an individual
• Genotype
– An individual’s DNA sequence or set of
genetic markers
• An individual’s genotype is responsible
for an individual’s phenotype
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How do you interpret a genetic
variant?
• What does a C-to-T
change mean?
• Smarter, prettier,
faster, stronger???
– No, just different
• Most variants are
neutral = no effect
– Genes make up only
~3% of genome and
genes make our
phenotype
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Genetic
anthropology
Types of studies
Peopling of
the Americas
Expansion out of Africa
• Population history
– Origins
– Relationships
• Populat’n movements
– Migrations/colonization
– Fission/fusion
• Ancient DNA
– Link ancestral and
descendant pops
Domestication
of the donkey
Modified from Balaresque et al. 2007
Origin and expansion
of Semitic speakers
• Disease
– Origin of disease
– Genetic basis of disease
Genetic and cultural
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Copyright 2011
components
to ethnicity
and health All rights reserved
How do we interpret genetic variants
to ask anthropological questions?
• Look at the patterns of genetic variation
• What has created the patterns of genetic variation?
– Evolutionary history of humans
Shriver and Kittles, 2004
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~ 200 kya
Slides by
C. Ryan
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2011
Raaum
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100-200 kya
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by 80 kya
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~ 60 kya
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45-60 kya
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by 45 kya
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40-50 kya
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~ 35 kya
Thanks, Ryan
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Human evolution encompasses both
demographic history and adaptation
• Demographic history • Adaptation
– Neutral markers
• Not subject to natural
selection
– Non-coding, ~97%
• Origin of anatomically
modern humans
• Neanderthal genetics
– Non-neutral markers
• Subject to natural
selection
– Genes, ~3% genome
• Skin color, eye color,
facial morphology,
race
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Genetic evidence for the origin of
modern humans
• H. sapiens are
characterized by very little
genetic variation relative to
other primates
– What does this suggest?
Jobling et al. 2003
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Genetic evidence for the origin of
modern humans
• H. sapiens are characterized by very little genetic
variation relative to other primates
– What does this suggest?
• Relatively recent evolution
• Selection
• Or, more recent research suggests it might relate to
generation time
– Longer generation time in humans → fewer opportunities for germ
line mutations → slower mutation rate → less variation/shallower time
depth
– Mutation rate follows generation time
• Humans < chimps
• hominoids < Old World monkeys
• Old World monkeys < marmosets
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Genetic evidence for the origin of
modern humans
• Greatest genetic diversity is in
African populations
– Consistent w/ out-of-Africa theory
of human origin
• Most genetic variation in
humans is within populations,
not between populations
– ~85% w/i pops
– ~5% b/t pops on same continent
– ~10% b/t pops on different
continents, i.e. races
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Types of DNA
• Mitochondrial (mtDNA)
– no recombination
– high copy number (but
haploid)
– maternal inheritance
– high mutation rate
– studied first
– large comprehensive
database
Holland & Huffine 2001
• Nuclear DNA (nDNA =
autosomes + sex
chromosomes)
–
–
–
–
–
–
homologous recombination
single genome/diploid cell
biparental inheritance
variable mutation rate
studied more recently
multiple studied loci make
comparisons more difficult
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Mitochondrial Eve
- the mother of us all
• What is the
mitochondrial
Eve theory?
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Mitochondrial Eve
- the mother of us all
• What is the
mitochondrial
Eve theory?
– The idea that we
all trace back to
a single woman
• How can this
be?
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Mitochondrial Eve
- the mother of us all
• What is the
mitochondrial Eve
theory?
– The idea that we all
trace back to a
single woman
• How can this be?
– B/c mitochondrial
DNA does not
recombine
– We have infinite
nuclear ancestors
b/c nuclear DNA
does recombine
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If we can all trace our maternal lineage
back to a single women, then why
don’t we all have the same mtDNA?
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If we can all trace our maternal lineage
back to a single women, then why
don’t we all have the same mtDNA?
• MUTATION!
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Race
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Genetics and Race
• What can biology/genetics tell us about race?
• What can biology/genetics tell us about
ourselves?
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What can genetics tell us about race?
• There is no genetic or biological definition for what we
refer to as ‘race’ in humans
• There is no Caucasian gene, no African gene, no Asian
gene
• Is there one gene that distinguishes one race from
another? No.
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Human evolution and genetic variation
• Anatomically modern humans have
been evolving for over 200,000 years
and we are still evolving
• There are no ‘pure’ human stocks and
there never were
• No populations are more highly
evolved than others
• Human populations are too closely
related to be considered subspecies
• There is a continuum of genetic
variation across the globe
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What genes do we have?
• We have genes for:
–
–
–
–
ATP/energy production
DNA repair
Metabolic pathways
…
• No one has ever identified a gene for:
–
–
–
–
–
–
Intelligence
Athleticism
Musical ability
Language ability
Work ethic
Personality
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How do you interpret a genetic
variant?
• What does a C-to-T
change mean?
• Smarter, prettier,
faster, stronger???
– No, just different
• Most variants are
neutral = no effect
– Genes make up ~2% of
genome
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But there are different frequencies
of alleles in different populations
• Alleles differ in frequency between people and
populations, genes don’t differ in frequency
– Gene – DNA sequence that encodes a protein
– Allele – one of several alternative forms of a DNA sequence
(can be coding or non-coding)
Human chromosomes, Genetics,
Hartl and Jones, 2000
Mulligan, Copyright 2011
Types of alleles, Genetics, C.
Hartl
and Jones, 2000
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But differences in allele frequencies
doesn’t mean populations fall into
racial categories
• Most genetic variation among humans
occurs within populations, not between them
• Variation in gene frequency is distributed
continuously, or clinally, in response to
selection or genetic drift
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Most genetic variation among humans
occurs within populations, not between
them
Total Species
(100%)
Between Regional
Populations
(10%)
Within Regional
Populations
(90%)
Between Local
Populations Within
Regional Populations
(5%)
Between Individuals
Within Local Populations
(85%)
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But differences in allele frequencies
doesn’t mean populations fall into
racial categories
• Most genetic variation among humans
occurs within populations, not between them
• Variation in gene frequency is distributed
continuously, or clinally
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Variation in skin color in 22 populations
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• Bad sampling (A) can give the illusion of clusters,
but good sampling (B) shows a cline in frequencies
Serre, D., and S. Paabo. 2004. Genome Research 14:1679-1685.
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But we look different!
• We can see differences between people
– e.g. dark-skinned, light hair, etc
• But, only a few genes (out of ~20,000) determine
skin color, hair color, etc. so it doesn’t take many
variants to make us look different
– The differences are literally only ‘skin deep’
– Skin color is controlled by levels of melanin
– Three main genes for melanin production
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What can genetics tell us about ourselves?
• For a fee, lots of companies will tell you
something about your ancestors based on a DNA
sample
– National Genographic, DNA Ancestry Project, DNA
Tribes, Ancestral Origins
• https://www.gtldna.net/ancestral-origins-dnaancestry.html?src=google&gclid=CMaqk6jzv58CFQmdnAodO
Tr0zw
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Neanderthal (+ other archaics)
genetics
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First publication of DNA
sequences from a Neanderthal
• Sequence data from Neanderthal
type specimen, found in Neander
Valley, Germany in late 1800s
– Krings et al. 1997 – mtDNA HVRI
sequence
– Krings et al. 1999 – mtDNA HVRII
sequence
Holland & Huffine 2001
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Neanderthal genetics
What is the evidence against
interbreeding between Neanderthals
and modern humans?
Jobling et al. 2003
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Neanderthal genetics
Jobling et al. 2003
• Mitochondrial DNA data show that the
majority of Neanderthal genetic variation
lays outside modern human genetic
variation
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Jobling et al. 2003
Neanderthal genetics
• Mitochondrial DNA data show that the
majority of Neanderthal genetic variation
lays outside modern human genetic
variation
• Phylogenies show Neanderthal as an
outgroup
Noonan 2010
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Jobling et al. 2003
Neanderthal genetics
• Mitochondrial DNA data show that the
majority of Neanderthal genetic variation
lays outside modern human genetic
variation
• Phylogenies show Neanderthal as an
outgroup
• MRCA b/t Neanderthal and humans is 4x
older than MRCA of humans
Noonan 2010
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Jobling et al. 2003
Neanderthal genetics
• Means that Neanderthal mtDNA gene pool
evolved for a long time, isolated from
humans, and there is no support for a
Neanderthal contribution to modern
human mtDNA
Noonan 2010
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What about nuclear DNA?
Represents 3 billion bases, not 16 thousand
• Green et al. (2010) published draft nuclear
genome sequences of 3 Neanderthals
– Posits 1-4% Neanderthal admixture in
Europeans and Asians
– Since it occurred in both Europeans and
Asians, likely to have occurred before those
groups split, i.e. ~50-80 kya
– No Neanderthal DNA in Africans
– Expected difference between
mitochondrial and nuclear DNA
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Denisova
• In 2008, a hominin bone fragment
was discovered in the Denisova cave
in southern Siberia’s Altai mountains
– Child’s finger bone scattered among stone tools
and bone implements in layer dated to 48-30 kya
• It was believed that modern humans
and Neanderthals were the only
hominins present there at the time
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Phylogenetic analysis
• Denisova mtDNA lineage
branches much earlier than
human and Neanderthal
lineages
– Most recent common ancestor
(MRCA) between humans and
Denisovans is ~1mya
– MRCA is twice as old as MRCA of
humans and Neanderthals
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Phylogenetic analysis
• Denisova mtDNA lineage
branches much earlier than
human and Neanderthal
lineages
– Most recent common ancestor
(MRCA) between humans and
Denisovans is ~1mya
– MRCA is twice as old as MRCA of
humans and Neanderthals
• Denisova can’t be H erectus b/c H
erectus wasn’t in mainland Asia ~40
kya and H erectus left Africa ~2 mya
– Denisova must have been in Africa ~2
mya to share a common ancestor with
modern humans and Neanderthal
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– New hominin! ID’ed by DNA!!
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What about nuclear DNA?
• Changes phylogeny – Denisovan closer to
Neanderthal than modern humans
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What about nuclear DNA?
• Changes phylogeny – Denisovan closer to
Neanderthal than modern humans
• 4-6% admixture in Southeast Asians
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Major paradigm shift
• We do have Neanderthal DNA in us!
• And Denisovan, another archaic hominin
• Recent papers propose admixture from possibly
two more, unidentified archaic hominins
• Allele in a gene in our immune system has
recently been identified as coming from
Neanderthals and conferring a selective
advantage (Mendez et al. AJHG, 2012)
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Current status
• Some debate about archaic admixture vs
ancient population substructure in Africa
(> 100-200kya) that could create signal of
archaic admixture but is really just
separate gene pools in Africa, only one of
which left and gave rise to European and
Asians
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Cro-Magnon, n=2
Conclusion - Modern humans clearly group w/ Cro-Magnon and show
no shared ancestry with Neanderthal
Cro-Magnon
Neanderthal
Caramelli et al. 2003
Multidimensional scaling of
HVRI sequences of 60
modern Europeans (filled
squares), 20 modern nonEuropeans (filled circles), 4
Neanderthals (open
diamonds), Lake Mungo
specimen (open circle), and
Paglicci specimens (open
squares)
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