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Human Genetics, part II Liisa Kauppi (Keeney lab) Human populations: origins Implications of population 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 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 Human population history Genetic evidence is always considered alongside linguistic, anthropological and archeological evidence demic diffusion or cultural diffusion?

Two phenomena influencing gene/allele frequencies: Founder effect Small number of individuals settles new area, 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

Additional forces influencing allele frequencies: ・Genetic drift random effects, stronger when population size is 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? Mixing or replacement?

Classical marker studies Differences in allele frequency genetic distances Genetic diversity outside of Africa Classical marker studies Differences in allele frequency genetic distances Genetic diversity outside of Africa is a subset of diversity in Africa Based on 120 protein-coding genes in 1, 915 populations Cavalli-Sforza & Feldman (2003) Nature Genet. 33, 266 -275

Human genetic diversity is evenly distributed Most variation between populations Most variation within populations Human genetic diversity is evenly distributed Most variation between populations Most variation within populations Templeton (1999) Am. J. Anthropol. 100, 632 -650

A large fraction of global human diversity is contained within populations Within population Median, A large fraction of global human diversity is contained within populations Within population Median, all 84. 6 autosomal polymorphisms Between populations, continents within continent 5. 1 9. 9 AMOVA (analysis of molecular variance)

Father Mother Son Courtesy of Mark Jobling Father Mother Son Courtesy of Mark Jobling

Non-recombining systems Y chromosome “haplogroups” “mitotypes” 1 3 4 2 Molecular clocks Most recent Non-recombining systems Y chromosome “haplogroups” “mitotypes” 1 3 4 2 Molecular clocks Most recent common ancestor

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

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

Phylogenetic trees commonly indicate a recent origin in Africa Y chromosome Phylogenetic trees commonly indicate a recent origin in Africa Y chromosome

Y haplogroup distribution Jobling & Tyler-Smith (2003) Nature Rev. Genet. 4, 598 -612 Y haplogroup distribution Jobling & Tyler-Smith (2003) Nature Rev. Genet. 4, 598 -612

An African origin An African origin

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

Anatomically modern humans arrived in Europe via Asia 35, 000 - 40, 000 years Anatomically modern humans arrived in Europe via Asia 35, 000 - 40, 000 years ago. Europeans are descendants of: Paleolithic hunters and gatherers Neolithic farmers Upper Paleolithic Late Paleolithic Neolithic

Modern human mt. DNA is distinct from Neanderthal mt. DNA Neanderthal people lived in Modern human mt. DNA is distinct from Neanderthal mt. DNA Neanderthal people lived in Europe 300, 000 - 30, 000 years ago Krings et al. (1997) Cell 90, 19 -30

Different genetic marker systems tell different stories Sample from La Plata, Argentina 45. 6% 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, 543 -57

More recent reshaping of diversity a cluster of closely related lineages • ‘Star cluster’ More recent reshaping of diversity a cluster of closely related lineages • ‘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, 717 -721

Are you a descendant of Genghis Khan? http: //www. oxfordancestors. com/genghis_khan. html Paternal Clan Are you a descendant of Genghis Khan? http: //www. oxfordancestors. com/genghis_khan. html Paternal Clan certificate: Matriline service Seven Daughters of Eve certificate

Lactase persistence • All infants have high lactase enzyme activity to digest the sugar 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 Population history and mapping of genetic diseases

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

What’s special about isolated populations? In a more “inbred” population, patients suffering from a What’s special about isolated populations? 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) Rare recessive diseases maybe much more prevalent

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

Admixture Mapping • “Admixed” population is homogeneous but each individual’s genome is a mosaic 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 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 (Hap. Map SNPs) • Must have at least 10% admixture Smith and O’Brien (2005) Nat Rev Genet 6, 623 -632

Admixture mapping Disease allele must have different frequencies in populations 1 and 2 Darvasi Admixture mapping Disease allele must have different frequencies in populations 1 and 2 Darvasi and Shifman, Nature Genetics 37, 118 - 119 (2005)

Assigning ancestry of chromosomal segments Smith and O’Brien (2005) Nat Rev Genet 6, 623 Assigning ancestry of chromosomal segments Smith and O’Brien (2005) Nat Rev Genet 6, 623 -632

Admixture Mapping • Patient cohort of black Americans with multiple sclerosis (MS) • MS 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

Pharmacogenetics “individualized medicine/therapy” Optimize drug efficacy and minimize toxicity Clinical trial: GSK 3 -beta Pharmacogenetics “individualized medicine/therapy” Optimize drug efficacy and minimize toxicity Clinical trial: GSK 3 -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 drugmetabolism status “It is no surprise that skin pigment is a lousy surrogate for drugmetabolism status or most any aspect of human physiology. ” Mc. Leod (2001), News and Views commentary on “Population genetic structure of variable drug response”, Nature Genetics 29, 265 - 269 group fluidity and overlap! 14% of black American vs. 49% of White Americans benefiting from angiotensin-converting enzyme inhibitor for heart failure Yet - Bi. Dil is now the first FDA approved drug for use in a specific ethnic group