MOLECULAR GENETICS 2006
Tuesday November 28:
Human Genetics, part II
Liisa Kauppi (Keeney lab)
RRL-1129
Phone 639 5180
Email kauppiL@mskcc.org
Recommended reading:
Redon R et al. (2006) Global variation in copy number in the human genome. Nature
444: 444-454
Green RE et al. (2006) Analysis of one million base pairs of Neanderthal DNA. Nature
444: 330-336
Discussion paper:
Freedman ML et al. (2006) Admixture mapping identifies 8q24 as a prostate cancer risk
locus in African-American men. PNAS 103: 14068-14073
What can genetic information tell us about human history and evolution?
Genetic evidence is always considered alongside linguistic, anthropological and
archeological evidence. DNA can be a powerful tool when trying to answer whether
certain technologies, ideas etc. spread by demic diffusion or cultural diffusion. Demic
diffusion means migration of people, so it should be detectable using DNA markers.
Two phenomena influencing gene/allele frequencies:
Founder effect
Small number of individuals settles new
area, then population grows
Bottleneck effect
Population size collapses due to e.g.
famine or epidemic
 genetic variability decreases
Additionally, genetic drift, gene flow and selection can influence allele frequencies. All
three forces have stronger effects if the population size is small.
There are two hypotheses about the origins of modern humans:
A) out-of-Africa hypothesis
- anatomically modern humans evolved in Africa c. 300,000 years ago and migrated to
populate the rest of the world replacing the existing H. erectus population.
- the various ‘archaic sapiens’ species could not and did not interbreed
- common human ancestor << 1 mya
B) multiregional hypothesis
- H. erectus left Africa > 1mya and migrated to Europe and Asia. Change to H. sapiens
occurred gradually throughout the whole of the H. erectus population.
- requires a common human ancestor >1 mya
Mixing or replacement?
Classical marker studies

Di f f e re n c e s i n a l l e l e f re q u e n c y
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.
G enet ic diver sit y O UTSI DE of Af r ica is a subset of diver sit y I N Af r ica
Ba s
ed on120 p
r o t e in
- c o d in g g e n e
s in 1
, 915 p
o p u la tio n s
Ca v a li- Sf o r z a
& F
e ld m a n ( 2 0 0 3
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Na tu r e G e
net .
33
,
66- 275
2
Human genetic diversity is evenly
distributed
Most variation
between
populations
Most variation
within
populations
Templeton (1999) Am. J.
Anthropol. 100, 632-650
Clustering of 210 unrelated individuals
assuming three ancestral populations, obtained from 67 biallelic CNVs
FST = 0.11
From Redon et al. (2006), Nature 444, 444-454
Commonly used markers in human population genetics are “classical” (protein) markers,
autosomal polymorphisms and Alu insertions, Y chromosomal polymorphisms and
mitochondrial polymorphisms. Inheritance of autosomal DNA is markedly different from
Y chromosomal and mitochondrial DNA:
Two genetic systems have been particularly useful for studying human population
genetics: Y-chromosomes (father-to-son inheritance) and mitochondrial DNA (mtDNA,
mother-to-offspring inheritance). Both are virtually non-recombining entities, apart from
the tips of the Y-chromosome called the pseudoautosomal regions. This property means
that evolutionary trees of the can be constructed more easily; each new mutation will
create a new branch in the phylogeny.
Non-recombining systems
Y chromosome Тhaplogroups У
ТmitotypesУ
1
2
3
4
Molecular clocks
Most recent common ancestor
MtDNA has been the most popular system. There are thousands of mtDNA copies per
cell which allows analyses even from old and degraded samples.
Human mtDNA studies can be summarized as follows:
1)There is a greater amount of mtDNA variation in Africa in comparison to populations
in other parts of the world
2) there are variations that are unique to Africa.
Both data on autosomal DNA markers and Y chromosomal markers are in good
agreement with the two statements above.
Conclusions:
1. Modern humans originated in Africa
2. There was a subsequent spread to other parts of the Old World replacing earlier
hominid populations.
Y chromosome lineages - fathers to sons
ТY chromosomal
AdamУ and
Тmitochondrial Eve У
were not alone!
Courtesy of Mark Jobling
Phylogenetic trees commonly
indicate a recent origin in Africa
90 (50 - 130) KYA, Hammer and Zegura
59 (40 - 140) KYA, Thomson et al.
90
69 (56 - 81) KYA, Hammer and Zegura
40 (35 - 89) KYA, Thomson et al.
80
KYA
70
60
50
40
30
20
10
0
A
B C D E F* G H
I
J K* L M N O P* Q R
Y chromosome
Y haplogroup distribution
A
B C D E F* G H
I
J K* L M N O P* Q R
Jobling & Tyler-Smith (2003) Nature Rev. Genet. 4, 598-612
An African origin
A
B C D
E F* G H
I
J K* L M N O P* Q R
In Europe, there is a southeast to northwest cline in Y
haplogroups
Q uickTim e™ and a
TI FF ( LZW) decom pr essor
ar e needed t o see t his pict ur e.
Gradients of allele
frequencies indicate
migration of people
Anatomically modern humans arrived in Europe via Asia 35,000 - 40,000 years ago.
Europeans are descendants of:
Paleolithic hunters and gatherers
Neolithic farmers
Q uickTim e™ and a
TI FF ( LZW) decom pr essor
ar e needed t o see t his pict ur e.
Upper Paleolithic
Late Paleolithic
Neolithic
Furthermore, there is little evidence that Neanderthal people interbred with anatomically
modern humans (mtDNAs are too different – but see paper in Recommended Reading).
Modern human mtDNA is distinct from Neanderthal mtDNA
Krings et al. (1997) Cell 90, 19-30
But see recent paper by Green RE et al., Nature 444, 330-336
1 Mb of Neanderthal DNA sequenced -Тmay suggest gene flow between modern
humans and Neanderthals
У
More recent reshaping of diversity
Ґ Ф
Star clusterХY haplotype originated in/near Mongolia ~1,000 (700-1,300) years ago
Ґ Now carried by ~8% of men in Central/East Asia, ~0.5% of men w orldw ide
Ґ Suggested association w ith Genghis Khan
Zerjal et al. (2003) Am. J. Hum. Genet . 72, 717-721
Lactase persistence
Ґ All infants have high lactase enzyme activity
to digest the sugar lactose in milk
Ґ In most humans, activity declines after
weaning, but in some it persists:
LCT*P
How does this relate back to mapping of genetic diseases?
Q uickTim e™ and a
G r aphics decom pr essor
ar e needed t o see t his pict ur e.
LD is a measure of allelic association in a population
Disease haplotypes shorten from
one generation to the next
markers are in LD (ТLD blockУ)
So, all humans are related if you look back far enough. However, in populations that
derive from a relatively small number of founding individuals, people are on average
more related to each other than in an “outbred” population. Classic examples of small
and/or isolated populations include Finland, Iceland, Sardinia and the Amish people.
In such populations, patients suffering from a genetic disease are more likely to
share a common ancestor. Hence, it is more likely that there is just one type of causative
mutation (i.e. no allelic heterogeneity). These populations tend also to be younger, so LD
blocks are longer (less generations - less time for meiotic recombination), making them
ideal for initial genome scans in association mapping. Rare recessive disorders may be
much more prevalent.
If there are differences in allele frequency between populations, and some of these alleles
are involved in genetic disease, then prevalence of common diseases should also differ
between populations. For example blood group O is a moderate risk factor for infection
by Helicobacter pylori; in populations where O is more prevalent, peptic ulcers should be
more common. However, it is often difficult to make fair comparisons, as socioeconomic
status is a major factor in human health.
Admixture mapping makes use of inter-population differences in disease
incidence and may prove an important tool in mapping complex diseases. An “admixed”
population is homogeneous but each individual’s genome is a mosaic of segments from
different populations. For admixture mapping, the following requirements must be met:
1. Disease has to show a difference in incidence between the two “ancestral”
populations, (e.g. multiple sclerosis incidence is lower in Africans than
Europeans, hypertension higher in Africans than Europeans)
2. Polymorphic markers that differ in frequency in the ancestral populations
3. At least 10% admixture
Chromosomal segments (haplotypes) are then assigned to one of the two “ancestral”
populations. Patients should show an excess of the chromosomal segments from one
ancestral population (the one where disease is more prevalent) across the disease locus.
Admixture mapping
Disease
allele must
have different
frequencies
in populations
1 and 2
Darvasi and Shifman, Nature Genetics К37, 118 - 119 (2005)
Assigning ancestry of chromosomal segments
Smith and O ХBrien (2005) Nat Rev Genet 6, 623-632