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Transcript
Human Polymorphisms and
Genetic Anthropology
Prof. Connie J. Mulligan
Department of Anthropology
September 20, 2012
C. Mulligan, Copyright 2011
All rights reserved
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
All rights reserved
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
All rights reserved
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
All rights reserved
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
C. Mulligan, Copyright 2011
and Bartlett Publishers, Inc
All rights reserved
Genetic variants are changes in DNA
sequence between individuals
(A C-to-T variant is depicted in the DNA sequence below)
C. Mulligan, Copyright 2011
All rights reserved
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
C. Mulligan, Copyright 2011
All rights reserved
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
C. Mulligan, Copyright 2011
All rights reserved
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
C. Mulligan, Copyright 2011
All rights reserved
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
C. Mulligan,
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
C. Mulligan, Copyright 2011
All rights reserved
~ 200 kya
Slides by
C. Ryan
Mulligan, Copyright
2011
Raaum
All rights reserved
100-200 kya
C. Mulligan, Copyright 2011
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by 80 kya
C. Mulligan, Copyright 2011
All rights reserved
~ 60 kya
C. Mulligan, Copyright 2011
All rights reserved
45-60 kya
C. Mulligan, Copyright 2011
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by 45 kya
C. Mulligan, Copyright 2011
All rights reserved
40-50 kya
C. Mulligan, Copyright 2011
All rights reserved
~ 35 kya
Thanks, Ryan
C. Mulligan, Copyright 2011
All rights reserved
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
C. Mulligan, Copyright 2011
All rights reserved
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
C. Mulligan, Copyright 2011
All rights reserved
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
C. Mulligan, Copyright 2011
All rights reserved
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
C. Mulligan, Copyright 2011
All rights reserved
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
C. Mulligan, Copyright 2011
All rights reserved
Mitochondrial Eve
- the mother of us all
• What is the
mitochondrial
Eve theory?
C. Mulligan, Copyright 2011
All rights reserved
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?
C. Mulligan, Copyright 2011
All rights reserved
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
C. Mulligan, Copyright 2011
All rights reserved
If we can all trace our maternal lineage
back to a single women, then why
don’t we all have the same mtDNA?
C. Mulligan, Copyright 2011
All rights reserved
If we can all trace our maternal lineage
back to a single women, then why
don’t we all have the same mtDNA?
• MUTATION!
C. Mulligan, Copyright 2011
All rights reserved
Race
C. Mulligan, Copyright 2011
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Genetics and Race
• What can biology/genetics tell us about race?
• What can biology/genetics tell us about
ourselves?
C. Mulligan, Copyright 2011
All rights reserved
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.
C. Mulligan, Copyright 2011
All rights reserved
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
C. Mulligan, Copyright 2011
All rights reserved
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
C. Mulligan, Copyright 2011
All rights reserved
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
C. Mulligan, Copyright 2011
All rights reserved
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
All rights reserved
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
C. Mulligan, Copyright 2011
All rights reserved
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%)
C. Mulligan, Copyright 2011
All rights reserved
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
C. Mulligan, Copyright 2011
All rights reserved
Variation in skin color in 22 populations
C. Mulligan, Copyright 2011
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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.
C. Mulligan, Copyright 2011
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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
C. Mulligan, Copyright 2011
All rights reserved
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
C. Mulligan, Copyright 2011
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Neanderthal (+ other archaics)
genetics
C. Mulligan, Copyright 2011
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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
C. Mulligan, Copyright 2011
All rights reserved
Neanderthal genetics
What is the evidence against
interbreeding between Neanderthals
and modern humans?
Jobling et al. 2003
C. Mulligan, Copyright 2011
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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
C. Mulligan, Copyright 2011
All rights reserved
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
C. Mulligan, Copyright 2011
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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
C. Mulligan, Copyright 2011
All rights reserved
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
C. Mulligan, Copyright 2011
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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
C. Mulligan, Copyright 2011
All rights reserved
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
C. Mulligan, Copyright 2011
All rights reserved
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
C. Mulligan, Copyright 2011
All rights reserved
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
C. Mulligan, Copyright 2011
– New hominin! ID’ed by DNA!!
All rights reserved
What about nuclear DNA?
• Changes phylogeny – Denisovan closer to
Neanderthal than modern humans
C. Mulligan, Copyright 2011
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What about nuclear DNA?
• Changes phylogeny – Denisovan closer to
Neanderthal than modern humans
• 4-6% admixture in Southeast Asians
C. Mulligan, Copyright 2011
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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)
C. Mulligan, Copyright 2011
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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
C. Mulligan, Copyright 2011
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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)
C. Mulligan, Copyright 2011
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