Exam 3 Review

heterozygosity may reduce susceptibility to a diversity of diseases causing...

balancing selection

homoplasy

characteristic shared by set of species but not present in their common ancestor

hominin

group consisting of modern humans, extinct human species and all our immediate ancestors (including members of genera Homo, Auta, Paran, and Ardi)

"paleo diet"

idea that we have spent most of our evolutionary history as hunters and gatherers and adapting to those diets

comparative population history

lower genetic diversity in both Nean and Denisovans than humans--likely smaller population sizes

absence of protein (homozygous)

may be advantageous--reduced susceptibility to disease

introgression

movement of gene to one species into gene pool of another through repeated backcrossing of interspecific hybrid with one of its parent species

CNV gene loss

on average human has 100 genes with stop codons/frameshift indels on at least one chromosome with 20 genes absent from both chromosomes

mutations may reduce disease susceptibility causing...

positive selection

mutations may directly result in disease causing...

purifying selection

mutations may reduce susceptibility to some diseases but increase susceptibility to others causing...

purifying selection, positive selection, balancing selection, and neutral evolution

origins in Africa

-African origins--as modern humans left Africa, drift led to successive reductions in genetic diversity -African populations have highest genetic diversity of any living population -different waves from Africa: early (all the way to Australia) and second (modern Europeans and most modern Asians) -European populations likely composed of at least 3 genetic contributions from different arrivals -evidence suggests humans colonized Asia in 2 early waves (ancestors of Australians/Papuan and ancestors of East Asia)

major histocompatibility complex (MHC)

-MHC molecules bind specific repertoires of peptides with anchor amino acids that fit them exactly -individuals heterozygous at MHC loci are able to respond to greater range of pathogen peptides -NAs have less MHC genetic diversity (not just neutral diversity) -MHC also retains core functional diversity seen in populations worldwide

Neanderthal phenotypes

-Nean probably well adapted to environments -MC1R: skin and hair color variation in humans and many other species -N mutation can result in red hair and pale skin---variant shows reduction in MC1R activity

Duffy null allele example

-SNP in DARC promoter regions abolishes expression in red blood cells so fly cannot bind -nearly fixed in sub-Saharan Africa, nearly absent elsewhere likely due to positive selection -has no major clinical significance (in contrast to sickle cell allele) -recent realization that Duffy null allele is associated with lower white blood cell count -full range of potential consequences of Duffy null allele are unknown (however there is public health effect)

why consumption of milk without negative side effects

-access to milk as food source is advantageous -milk as alternative source of water (wouldn't account for selection in Europe) -calcium is essential for bones, vitamin D is important for Ca uptake

aDNA

-any DNA isolated in fossil in individuals that don't represent current populations on planet -DNA is degraded after death by endonucleases/other chemicals--normally kept separate but cell membranes break down -environmental breakdown (water, heat, UV) -cold and dry favors DNA preservation -some bones have DNA but very limited, exogenous DNA dominates, highly fragmented, and specific DNA bp damage

recent admixture between human populations

-average European genetic ancestry among African Americans is 20% -can learn about manner which admixture occurred from mtDNA and Y chromosome (although can't obtain ancestry)

Fst for human populations

-avg Fst between human populations: 15% -in contrast, Fst between chimp populations: 32% -thus 85% of total genetic variation in humans found within given population -standard for recognizing subspecies: 0.25 (75% overlap between populations)

thalassemia disorder

-beta form causes loss of function of hemoglobin proteins -loss of function of hemoglobin proteins (in red blood cells--carries oxygen) -caused by many different mutations--from gene deletions to amino acid mutations -disorder results in large numbers of red blood cells being destroyed which leads to anemia -homozygotes are fatal -heterozygotes sometimes results in anemia but protects against malaria -thalassemia incidence closely matches historical malaria incidence even down to very local levels (particularly common in sub-Saharan Africa and SE Asia but also particularly prevalent among Mediterraneans)

bifurcation diagram (G6PD)

-black circle represents core haplotype -each marker is opportunity for node -diagram divides or not depending on whether both or only one allele present -line thickness corresponds to the number of samples with that long-distance haplotype

*Templeton (2013)

-chimps divided into species while humans are not biologically -adaptive traits have been frequently used to define races in humans but they do not -humans have much genetic diversity but vast majority of diversity reflects individual uniqueness and not race

determining admixture between Nean and modern humans

-compare Nean and chimp genomes -identify bp where Nean is different from chimps -compare those bp (that diverged from chimps) to each of two human groups (individual of African and Euro ancestry) separately -calculate proportions of bp that are different -they should be similar amount of differences if no admixture (humans of any population should be equally divergent from Nean) -but if not similar, suggests admixture (bias in relationship to Nean) -1.3-2.7% of genomes of non-African humans may be from Nean

G6PD enzyme

-deficiency is most common in world -affects pathway affecting NADPH because this enzyme is only generator of NADPH in red blood cells -"A" variant is N mutation in exon 4 (results in reduction of enzyme activity and frequency is as high as 25% in African populations) -found on X chromosome so affects males more -symptoms: anemia (special sensitivity to fava beans b/c bean oxidants damage cells if not metabolized), infection with bacteria/viruses leads to anemia -but confers resistance to malarial infection (likely that oxidative stress in red blood cell environment creates toxic environment for parasites) -selection on the G6PD mutation associated with malaria resistance is ~2,500 years old.

changes in association between selected allele and nearby variants

-different chromosomes with different combos of SNPs -genetic drift (few generations): small increase in frequency -beneficial mutation ( few generations): large frequency of same haplotype--positive selection -genetic drift (many generations): high frequency SNP but in several different haplotypes (recombination) -frequency alone suggestive of recent positive selection but not sufficient

Native American populations

-disagreement over N and S NA populations--whether they split after humans entered Alaska or whether they represent separate migrations -sequenced genome of infant girl but her genetic info did not match either N or S early NAs -she belonged to separate NA population, the Ancient Beringians (separated from N and S NA populations earlier) -suggests that people may have entered continent in single migratory wave more than 20000 years ago

cM

-distance between chromosome positions for which we would expect an average of 1 recombination event per 100 generations -often used to infer distance along a chromosome but not a true physical distance -can track inheritance of specific markers to identify whether recombination occurred between them, but exact location between them is uncertain without sequence.

DARC gene

-encodes red blood cell antigen (Duffy or FY) is receptor for P. vivax infection -SNP in DARC promoter region abolishes expression in red blood cells -P. vivax almost completely absent where there's very high prevalence of Duffy negative phenotype

NAs/positive selection for alleles

-exceptionally high rates of porotic hyperostosis in pre-contact SW NAs (evidence of chronic/episodic malnutrition) -modern Navajo have among highest diabetes rates in world (1/4 adults) -recent very drastic shift in diet associated with forced relocations to lands that are unproductive for agriculture (reservations) -recently uncovered evidence of genomic signatures of positive selection for alleles associated with obesity/diabetes (high population differentiation and high extended haplotype homozygosity)

multiregional theory

-existence in different parts of world -mixed flow between them ultimately got to Homo sapiens -modern human characteristics arising at different times/places with gene flow between them

folate deficiency hypothesis (also skin cancer)

-folate: water-soluble form of vitamin B found in food, necessary in DNA replication -UV radiation destroys folate cells (photolysis) leading to birth defects (affecting CNS) and male infertility -darker skin blocks UV radiation better

genetic variants involved in skin color variation

-functional polymorphisms associated with skin color variation tend to be more strongly differentiated between populations -ASIP A8818G: melanin production -OCA2 A355G: melanosomal membrane protein (may help regulate pH) -TYR A192C: produces the enzyme tyrosinase which catalyzes the first 2 steps of melanin synthesis -MAPT C374G: involved in trafficking TYR -SLC24A5 A111G: regulates calcium levels in melanosome -HERC2: unclear but associated with OCA2 expression -MFSD12: lysosomal protein that modifies pigmentation in human melanocytes -ASIP and OCA2 play role in diversity of pigmentation -TYR, MAPT, and SLC24A5 have a predominant role in the light skin of Eur. but not E. Asians (suggests recent convergent evolution of lighter skin those populations)

skin color is poor indicator of overall genetic distance

-genes that contribute to visible traits such as skin, eye, and hair pigmentation show great allele frequency differences between continental gorups -geographic groups are more genomically similar to each other, on average, than they are similar in their pigmentation

genetic variation and race (summary)

-genetic differentiation between populations may be lower than what what we expect relative to outward observations -many outward indications of race reflect the more rare examples of positive selection, due to different environments -human populations are actually less genetically diverse than chimpanzee populations -human concepts of race are clearly historically and culturally real and relevant, but there is no biological/genetical support -genetic effects of ancestry may be relevant as well, even if differences between populations are relatively small

larger than avg genetic distance between populations

-genetic markers with FST values that are too large to be explained by neutrality -may include false positives

recombination hotspots

-genomic regions that exhibit elevated recombination rates, relative to neutral expectation -recombination rate within hotspots can be hundreds or thousands of times that of the surrounding region

cancers

-historical bias towards western, Caucasians in biomedical research, particularly cancer -wide variety of dietary lifestyle and environmental exposures, as well as genetic variation contributing to susceptibility/resistance

human/human and human/chimp genetic diversity

-humans are 99.9% genetically similar (excluding CNVs) -humans and chimps are 99.0% similar (1 SNP per 100 bp)

Neanderthal mtDNA

-humans are distinct from this one short sequence -human-Nean divergence estimated 660,000 (+/- 140k years) -we now have multiple Nean mtDNA genomes -no Nean mtDNA in any modern human samples--either from aDNA or modern studies (thousands of mtDNA genomes have been sampled) -Nean behavioral insights from aDNA: here, suggest male philopatry (stay in/ at least return to particular space) and female dispersal--males have identical mtDNA while females don't (males have identical mtDNA while females don't)

*Perry et al.

-identified 16 genomic regions associated with pygmy phenotype in Batwa -integrated haplotype score (IHS) and Fst calculated between Batwa and agricultural neighbors (the Bakiga) both values higher in for SNPs in Batwa for pygmy phenotype-associated regions (polygenic adaption) -these values in Baka hunter-gatherers and Nzebi and Nzime neighboring agriculturalists were not elevated -confirms that small body size confers advantage for tropical rainforest hunter-gatherers -Batwa-Baka comparison suggests pygmy phenotype convergence within Africa four primary conclusions -African pygmy phenotype has a genetic basis, rather than a solely environmental one, based on the positive correlation between stature and Bakiga admixture for Batwa individuals raised in Batwa communities -Batwa pygmy phenotype is likely polygenic in nature, as multiple genomic regions were highlighted by our admixture mapping analysis -Batwa pygmy phenotype was likely adaptive in origin, based on the elevated levels of population differentiation (FST) and haplotype-based signatures of selection (iHS) for SNPs within the regions identified by our admixture mapping analysis -pygmy phenotype evolved convergently within Africa, at least in part--the possibility of an additional, ancestral component cannot be excluded

long range haplotype test

-identify variants with high frequency and unexpectantly high levels of LD with flanking SNPs -measure LD at distance x from core region by calculating extended haplotype homozygosity -if = 0: no homozygosity (all extended haplotype different) -if = 1: complete homozygosity (all extended haplotypes are same) -test for positive selection involves finding a core haplotype with a combination of high frequency and high EHH, as compared with other core haplotypes at the locus -various core haplotypes at locus serve as internal controls for one another, adjusting for any unevenness in the local recombination rate.

variable selective coefficients

-important--age at which selection acts -dependent on current environmental context

Fst

-indication of population differentiation -measured by (variation between-variation within)/variation between -if = 1: complete differentiation (all of one population has allele A and all of other population has allele B) -if = 0: completely mixed, interbreeding freely (both population are half allele A and half allele B)

NA epidemics

-infectious disease epidemics in NA populations following European contact -population size declines in NAs due to widespread endemic disease (also warfare, enslavement, social disruption)

skin color and vitamin D hypothesis

-insufficient vitamin D intake/synthesis can affect bone structural integrity and health -melanin pigment can block UVB radiation, inhibiting vitamin D synthesis -UVB levels in tropics are sufficient for vitamin D synthesis, even with dark skin -insufficient vitamin D synthesis in more northern and southern latitudes with dark skin

Caspase-12

-involved in inflammation response pathway -premature stop codon results in pseudogene -mutation is in high frequency and in strong LD with surrounding SNPs -inactive form protects against over-response which may lead to sepsis and organ failure/death -selective advantage thought to be sepsis resistance in populations that experienced more infectious diseases as population sizes and densities increased

adaptive introgression of Nean to humans

-lack in Sub-Saharan African individuals--mixing occurred in Euro/East Asian areas -contrasting concepts of adaptive introgression, yet reduced fertility in hybrids -lower proportion of Nean ancestry on the X chromosome vs. the autosomes -genes expressed in the testes seem to have especially been targeted by purifying selection, against Nean alleles (maybe due to male hybrid sterility?)

Mycobacterium leprae (leprosy) and M. tuberculosis

-likely "jumped" from zoontic sources and became human pathogens within last 6,000 years -can sample mycobacteria in non-human primates and other animal around world to track genetic changes that occur as mycobacteria across from other species to humans (and back)

SNPs in skin color variation

-more differentiated between human populations than most SNPs in genome -skin color SNPs may reflect directional selection (while frequencies at most SNPs reflect genetic drift)

lactase persistence in Europeans and Africans

-mutation on chromosome 2, nearly 14000 bps upstream -C to T mutation -high Fst, frequency and EHH -selection began 5000-10000 years ago in Europe -selection occurred within last 7000 years in Africa -additional variants identified--lactase persistence has originated independently and separately

genetic variation within and between populations

-mutation: increases within, increases between -genetic drift: decreases within, increases between -gene flow: increases within, decreases between -natural selection (except balancing selection, which maintains variation within population): decreases within, increases between

CCR5 deletion

-on surface of white blood cells and recruits inflammatory cells -absence causes muted inflammatory responses -32 bp frameshift deletion -high frequency in European populations -co-receptor for HIV--without it, virus cannot get into cell -CCR5 deletion may have conferred resistance against plague

massive parallel sequencing

-only requires small amounts of input material -can work with short DNA fragments -produces lots of sequence data

thrifty genotype hypothesis

-our bodies not adapted for recent transition to agricultural diet and this diet is not healthy for us -strict application of logic of paleo diet not supported by current scientific evidence -our current selves reflect complex history of past adaptations to various diets and environments -hunters and gatherers (and even subsistence agriculturalists) may have lived under food-limited conditions--past natural selection for "thrifty" or slow metabolism, fat-depositing alleles may be associated with medical problems under modern diets of food excess

Denisovans

-pinky finger bone from 48-39 kya in Siberian region -sequenced DNA from bone assuming it was likely Nean but it wasn't--Denisovans are separating out from Nean and humans -Denisovans appear to have contributed small amount of genetic material ONLY to modern human Oceanic and SE Asian rainforest hunter-gatherer populations (part of first wave of modern humans out of Africa) -contributed to modern human genome but less so -there's also evidence of DNA that doesn't attribute to any of three species

two signs for positive selection

-positively selected mutations will show significantly larger than average genetic distance between populations -changes in association between selected allele and nearby variants

extended haplotype homozygosity (EHH)

-probability that 2 randomly chosen chromosomes carrying the core haplotype of interest are identical by descent (as assayed by homozygosity at all SNPs) for the entire interval from the core region to the point x -detects transmission of extended haplotype without recombination

convergent evolution

-process where organisms (not closely related) independently evolved similar traits as a result of having to adapt to similar environments -individual mutation is likely to occur in the same location in the genome only once but different mutations may have similar phenotypic effects -if we observe high frequencies of these traits/ mutations in similar environments, this is strongly suggestive (not proof) of natural selection

admixture

-result of interbreeding between two or more previously isolated populations within species -formation of hybrid population

partial loss (heterozygous)

-shows advantage -strong selection by malaria (many diseases in general) maintains high frequency of disease allele against purifying selection also acting on same disease allele

fragmentation of aDNA

-standard PCR doesn't work for aDNA (need at least 70-90 bp of DNA) -aDNA in fragments of <100-500 bp

damage in aDNA

-strand breakage does not occur evenly -high deamination rate, particularly on ssDNA -most current massively parallel sequencing approaches work with double stranded DNA but they involve an end repair step. -observable patterns of aDNA damage that can be accounted for in data analysis (know this phenomenon and account for it in analysis)

Out of Africa

-transition of Homo erectus to sapiens occurred in Africa -modern humans replaced them and migrated out -supported by modern DNA evidence (isolation by distance)

genetic hitchhiking

-when allele changes frequency not because it itself is under natural selection, but because it is near another gene that is undergoing selective sweep and that is on the same DNA chain.