COVID-19 Genetic Basis & Population Variability

• COVID-19 infection severity ranges from asymptomatic to death
• There is a genetic basis (alleles/genotypes) for population variability in COVID-19 infection and disease outcomes
• NCBI has information on human genes impacting tolerance/resistance to COVID-19
• The association results compare combined odds ratios (ORs)
• AFR: African
• EAS: East Asia
• EUR: European
• SAS: South Asian
• NS: Not significant
• The combined OR was calculated based on the COVID-19-associated SNPs set
• Variable n is the number of elements in the SNPs set with index k

Population Genetics

• Deals with the descriptions of heritable allele/genotype variations within a population through space and time
• Focuses on allele differences amongst populations
• Considers allele origin, frequency, and distribution in space and time
• Examines the evolutionary population dynamics through propagation of alleles and mutations

Mendelian Genetics Extension

• Mendelian genetics studies the population at the gene segregation level within a cross or family
• Population genetics studies alleles with varying frequencies at the population level
• Studies allele frequency changes within and between populations across different times and locations

Hardy-Weinberg Equilibrium (HWE)

• Assumes an infinitely large population size
• Assumes random mating patterns
• Assumes no selection, migration, or mutation
• Determines that the sum of allele frequencies squared is equal to the sum of all genotype frequencies
• (∑ allele frequencies)² = ∑ genotype frequencies
• This applies to a single point/locus with two versions/alleles
• (∑ allele frequencies)² = (p+q)² = 1² = 1 = p² + 2pq + q² = ∑ F(AA) + 2F(Aa) + F(aa)
• Where p is the frequency of allele A, and q is the frequency of allele a
• Describes and relates genetic frequency distributions, that assumes a stationary condition with no evolution
• HWE is the null model for goodness of fit analysis

Five Forces Impacting Allele Frequency

• Mutation
• Migration
• Selection
• Gene flow
• Gene drift

Allele Frequency Example Calculation

• Given a bird population with three different beak phenotypes which are controlled by a single gene with two alleles that are incompletely dominant
• p=F(A) and q=F(a) with p+q=1
• p=#A alleles/#total alleles
• p=(2x90+1x45)/(2x(90+45+15))
• q=#a alleles/#total alleles
• For q the equation is q=(1x45+2x15)/(2x(90+45+15))
• Calculations can be verified by confirming p+q=1

Hardy-Weinberg Equilibrium Chi Square Testing

• Given a population of 200 newts that are either poisonous(P), dominant, or not poisonous(p)
• Observed that 8 are not poisonous in this population
• To calculate allele frequencies:
• Observed
• 8 are pp so p² = (8/200)²
• So p = sqrt(8/200)²
• And q=1-p
• Predicted values assuming HWE (null hypothesis) are:
• AA=50x(AA)=50xp²
• Aa=50xF(Aa)=50x2pq²
• aa=50xF(aa)=50xq2
• To compare Chi squared compare observered and predicted values

Five Evolutionary Forces

• Genetic Drift: bottle neck and founding effects
• Random, non-selective change to the allele distribution(frequencies) of a population, more likely to occur in small populations
• Natural Selection
• When individuals have survival and reproduction differences, that are linked to their inherited traits
• Gene Flow + Migration
• Introduces new genetic material into a population
• Introduction of foreign alleles increasing genetic variation
• Sexual Selection
• Can take the form of competition between members of the same sex (intrasex selection)
• It can be in the form of selection of mates of the opposite sex (intersex selection)
• Mutation
• The primary source of genetic variation, which is essential for evolution.
• Mutations are randomly induced
• While beneficial mutations can spread through a population, many mutations are neutral or deleterious

The 1000 Genomes Project

• The 1000 Genomes Project existed as an international effort from 2008 to 2013
• The project cataloged human genetic variation by sequencing over 2,500 genomes from various ethnic groups
• It identifies genetic variants with a frequency of at least 1% in the studied populations
• The generated data has been made freely available to the scientific community, for research on genetic diseases, evolutionary biology and population genetics

Viewing Variations

• Use the NCBI Genome Viewer and select Homo sapiens
• Set the correct track options to view variation
• A user can explore single nucleotide polymorphism (dbSNP) and all (dbVar) variations

1000 Genomes Findings

• Conducted population sampling and polymorphism variant review within the sample
• It saw variants both private to a population (population specific) and shared across continents

The Influence of Migration

• Rare variants are typically recent and the sharing of them reveals aspects of population history
• Variants present twice across the entire 1000 genomes sample are called f2 variants, typically the most recent of informative mutations
• Most f2 variants will be found within the same population (mean 53%)
• Between-population sharing identifies recent historical connections or population structure

Global Population Genetics Trends

• Number of variants average from 4 to 5 million mutations per genome among populations.
• The number of singletons per genome ranges from 6,000 to 20,000 per genome.
• Singletons occur only once in the entire dataset of sequenced genomes and help genetic studies estimate aptitude for generating genetic diversity and evolution

Fixation Index

• Fixation index measures the degree of genetic differentiation, also known as fixation between populations
• Formula = Fst = (H₁ - H,) / H where Hand
• Heterozygosity of the total population and subpopulation are H₁ and H5 respectively
• FST measures the proportion of genetic variance that can be attributed to population differences and structure
• Helps scientists understand how much genetic variation comes from differences between populations
  • The Fixation index ranges from 0 to 1.
• 0 means no genetic differentiation (populations are genetically identical)
• 1 means complete genetic differentiation (populations are entirely distinct)
• Interpretation is relative to comparing two populations together
• If allele frequencies are very similar in two subpopulations, then the subpopulations are not differentiated and the fixation index will be close to 0
• If allele frequencies in two subpopulations are completely different, then populations are differentiated and the fixation index will be close to 1