Human Genetics, part II Liisa Kauppi (Keeney lab) Human populations: origins Implications of population history for disease mapping

The first demonstration of world-wide differences in human A, B and O allele frequencies (1919)

Human population history Genetic evidence is always considered alongside linguistic, anthropological and archeological evidence demic diffusion or cultural diffusion?

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 Two phenomena influencing gene/allele frequencies:

Additional forces influencing allele frequencies: ･ Genetic drift random effects, stronger when population size is small ･ Gene flow between neighboring groups ･ Selection For example infectious disease

Mixing or replacement?

Classical marker studies Based on 120 protein-coding genes in 1,915 populations Cavalli-Sforza & Feldman (2003) Nature Genet. 33, Genetic diversity outside of Africa is a subset of diversity in Africa Differences in allele frequency  genetic distances

Human genetic diversity is evenly distributed Most variation between populations Most variation within populations Templeton (1999) Am. J. Anthropol. 100,

Within population Between populations, within continent Between continents Median, all autosomal polymorphisms A large fraction of global human diversity is contained within populations AMOVA (analysis of molecular variance)

Father Mother Son Courtesy of Mark Jobling

Non-recombining systems Y chromosome “haplogroups” “mitotypes” Molecular clocks Most recent common ancestor

mtDNA Maternal - language Y chromosome Paternal - surname Sociocultural factors Patrilocality in most human populations Polygamy Colonizations: mostly males

Courtesy of Mark Jobling Y chromosome lineages - fathers to sons “Y chromosomal Adam” and “mitochondrial Eve” were not alone!

Phylogenetic trees commonly indicate a recent origin in Africa Y chromosome

Y haplogroup distribution Jobling & Tyler-Smith (2003) Nature Rev. Genet. 4,

An African origin

In Europe, there is a southeast to northwest cline in Y haplogroups Gradients of allele frequencies indicate migration of people

Europeans are descendants of: Paleolithic hunters and gatherers Neolithic farmers Late Paleolithic Upper Paleolithic Neolithic Anatomically modern humans arrived in Europe via Asia 35, ,000 years ago.

Modern human mtDNA is distinct from Neanderthal mtDNA Krings et al. (1997) Cell 90, Neanderthal people lived in Europe 300, ,000 years ago

Different genetic marker systems tell different stories Sample from La Plata, Argentina 45.6% native American maternal lineages 10.6% native American paternal lineages Autosomal markers: 68% European, 26% native American, 7% West African Martinez et al., 2004, Hum Biol 76,

More recent reshaping of diversity ‘Star cluster’ Y haplotype originated in/near Mongolia ~1,000 (700-1,300) years ago Now carried by ~8% of men in Central/East Asia, ~0.5% of men worldwide Suggested association with Genghis Khan (social prestige as a selective force) Zerjal et al. (2003) Am. J. Hum. Genet. 72, a cluster of closely related lineages

Are you a descendant of Genghis Khan? Paternal Clan certificate: Matriline service Seven Daughters of Eve certificate

Lactase persistence All infants have high lactase enzyme activity to digest the sugar lactose in milk In most humans, activity declines after weaning, but in some it persists: LCT*P

Population history and mapping of genetic diseases

Founder effect People are on average more related to each other than in an “outbred” population “Unrelated” individuals… All humans are related if you look back far enough …but some are more related than others

In a more “inbred” population, patients suffering from a disease are more likely to share a common ancestor More likely to have just one type of causative mutation (no allelic heterogeneity) In a younger population, LD blocks are longer (less generations - less time for meiotic recombination) What’s special about isolated populations? Rare recessive diseases maybe much more prevalent

The first replicated ABO association study (1954) Mechanism: ABO blood group binding adhesin BabA in H. pylori

Admixture Mapping “Admixed” population is homogeneous but each individual’s genome is a mosaic of segments from different populations May be used to map disease loci –multiple sclerosis susceptibility (Reich et al. 2005)

Admixture Mapping - requirements Disease has to show a difference in incidence between the two “ancestral” populations, for example: multiple sclerosis  in Africans vs. Europeans, hypertension  in Africans vs. Europeans Must have polymorphic markers that differ in frequency in the ancestral populations (HapMap SNPs) Must have at least 10% admixture Smith and O’Brien (2005) Nat Rev Genet 6,

Admixture mapping Darvasi and Shifman, Nature Genetics 37, (2005) Disease allele must have different frequencies in populations 1 and 2

Smith and O’Brien (2005) Nat Rev Genet 6, Assigning ancestry of chromosomal segments

Admixture Mapping Patient cohort of black Americans with multiple sclerosis (MS) MS  in Africans vs. Europeans Admixture: 20% European, 80% African Assign chromosomal segments (haplotypes) as “African” or “European” Patients with MS should show an excess of “European” chromosome segments across disease locus

“individualized medicine/therapy” Optimize drug efficacy and minimize toxicity Pharmacogenetics Clinical trial: GSK3-beta gene and bipolar disorder SNP (-50 T/C) in promoter region Recurring episodes reduced with lithium in C/C homozygotes and C/T heterozygotes Benedetti et al., (2005) Neurosc Lett 376, 51-55

“It is no surprise that skin pigment is a lousy surrogate for drug- metabolism status or most any aspect of human physiology.” McLeod (2001), News and Views commentary on “Population genetic structure of variable drug response”, Nature Genetics 29, Yet - BiDil is now the first FDA approved drug for use in a specific ethnic group group fluidity and overlap! 14% of black American vs. 49% of White Americans benefiting from angiotensin-converting enzyme inhibitor for heart failure