2 Definition and Scope of Population Genetics

Ms. Gangaina Kameih

TABLE OF CONTENTS

1. Introduction

2. Origin and growth of Theories on Evolution

3. Definition and scope of Population genetics

3.1. Evolutionary forces shaping genetic variation

3.1.1Mutation

3.1.2 Genetic Drift

3.1.3 Natural Selection

3.1.4 Gene Flow or Migration

3.1.5 Recombination

3.1.6 Non-random Mating or Assortative Mating

3.2. A short history of population genetics

3.3. Mathematical Models of population genetics

Learning outcomes

After studying this module:

You would know the origin and growth of Theories in Evolution.
You would know the evolutionary forces that shape the genetic variation.
You shall be able to understand the definition and scope of population genetics with their history and the mathematical models.

1. Introduction

Modern humans evolved in Africa about 200kya and migrated across different regions of the world (Lachance & Tishkoff, 2013). They traversed through diverse spatial conditions and underwent modifications to adapt with environmental pressures for successful survival and perpetuation leaving traces of variation in the human genetic structure. Studying the genetic structure of human populations is fundamental to the understanding of these modifications. Knowledge of structuring among human populations is important to find out patterns of diversity in them in the light of external pressures to help understand adaptation. A coherent pattern among evidences generated by ethno-history, linguistic, geographic and genetic investigations is crucial for understanding the dynamics of human population structure. However, genetic evidences have the advantage of bearing imprints of the earliest events in evolutionary time (Jobling et al., 2013). Genetic evidences are given by patterns in variations in complete or specific regions of the human genome that constitute genetic diversity of a population when a sample of individual genomes is scanned. Investigating genetic variations in isolation from environmental factors leads to an incomplete understanding of this diversity. An anthropological approach is, however, useful in gaining insights on genetic diversity by considering a range of factors to apportion the quantity of variation observed.

Anthropology is the study of humans in spatially and temporally varied conditions. It involves studying both the cultural and biological attributes of human populations and the interplay between them. The intra-population and inter-population differences in cultural and biological aspects are studied to deduce patterns in diversity. The insights obtained are used to draw inferences on how evolution has shaped humans.

Evolutionary forces subject human populations to changes in biological traits that are inherited through generations. Studying these biological differences among human populations in an evolutionary framework comes under the purview of biological anthropology in general and population genetics in particular. It deals with assessment of genetic differences underlying biological traits to comprehend the allele and genotype frequencies in populations and predicting the way they would change over a period of time. The alterations in frequencies are used in mathematical models to comprehend the interplay between different micro-evolutionary forces. The patterns of genetic variation are used to test hypothesis on demographic events that have occurred during the history of modern humans.

2. Origin and growth of Theories on Evolution

The ground for the mechanism of evolution was laid down by evidences on biological diversity compiled by naturalists much before Charles Darwin proposed his theory of evolution. However the actual mechanism responsible for biological change was not known. The first noteworthy attempt to explain the process of evolution is found in the theory of acquired characteristics laid down by Jean-Baptiste Lamarck. He reasoned that organisms adjust to their environments during their lifetime and the resulting modified traits are passed on to the offspring making them better adapted. Although he correctly emphasized on the presence of animal-environment interaction, he was wrong about an evolutionary change occurring in an organism’s lifetime. Another ideology that impressed upon Darwin was based on the works of the geologist Charles Lyell who endorsed the idea that a complete understanding of the history of earth requires knowledge of ancient geological changes.

Darwin’s theory of evolution was propelled by the works of naturalists, geologists and population theorists. A large body of evidences from biogeography, embryology and anatomy however, helped him formulate the theory of evolution by natural selection. In his work On the Origin of Species (Darwin 2009), he laid down three observations and proposed two implications. The first observation was that all organisms have the ability of explosive population growth that can use up all the food resources available. This idea was borrowed from An Essay on the Principle of Population (Malthus, 1798). A second observation was that the population growth was, however, stable. Basing on these two observations he deduced that populations do not attain their maximum potential to reproduce. Only few individuals who successfully reach a reproductive age were selected for. Darwin observed that minute differences existed even among individuals in the same population. He implied that some of these variations might be favorable as against the others and support perpetuation of the organism. Darwin had received similar inputs from the field biologist Alfred Russel Wallace on the mechanism of evolution. In essence, species could be perceived as entities in constant interaction with their environment and responding to changes therein. In this interaction, natural selection filtered out the traits that did not favor the organism’s reproductive success.

The successful transmission of adaptive traits to the offspring is necessary for the former to spread in a population. Darwin’s theory of evolution by natural selection fell short of a plausible explanation for this hereditary transmission. He understood that natural selection operated in a population due to the variations present in it but could not explain the origin of this variation.

Meanwhile, an Austrian monk, Gregor Johann Mendel gave the idea of hereditary transmission of traits for inheritance through observations made during his breeding experiments on Pisumsativum. He recorded the pattern of transmission followed by different characters across generations. Basing on these observations he proposed the particulate nature of hereditary transmission. He postulated that in organisms hereditary characteristics are controlled by a pair of “factors” that were particulate in nature. He further asserted that in the event of existence of two different factors for a characteristic, the one dominant is expressed while the factor which is not expressed is the recessive. He was fortunate to have examined dominant traits only. The law of segregation was proposed to explain the dynamics of factors during gamete formation. Mendel proclaimed that the paired factors undergo random segregation with each gamete receiving a factor with equal probability for either factor. The last of Mendel’s laws called the law of independent assortment states that the segregating pairs of factors assort independent of one another. Mendelian laws of genetics laid the foundation for genetic research by giving a roadmap for the identification of phenotypes as genetic features by following there pattern of inheritance. However, Mendel’s work was neglected initially and rediscovered by De Vries, Correns and Tschermark independently in 1900 (Correns, 1900; Vries, 1900; Tschermark, 1900) through breeding experiments in other species. Similar findings were obtained from several other works on different species. The rediscovery of Mendel’s laws was widely known but could not lead to provide a unifying theory for speciation. The reason was that the geneticists aware of evolutionary theories rejected the gradual evolution through natural selection acting on variants. However, some geneticists did support the naturalist’s interpretation of gradual evolution but were not known to the latter group (Mayr, 2004). The mutational theories given by geneticists were refuted with the emergence of the mathematical field of population genetics in 1910 under the supervision of Thomas Hunt Morgan.

3. Definition and scope of Population genetics

Population genetics is the branch of biology that provides deepest understanding of how evolutionary changes occur. Population genetics can broadly define as the branch of genetics concerned with the hereditary makeup of populations. It can also refers to the study of gene and genotype frequency and predicting the way these frequencies change or remain constant under the combined influence of various factors, over time, within and between populations. Population geneticists usually focus their attention on a Mendelian population, which is a group of interbreeding, sexually reproducing individuals that share a common gene pool (Dobzhansky, 1950).

Population genetics is relevant today as its theory along with technological inputs from the other branches such as molecular genetics and bioinformatics is contributing immensely to document the allele frequencies at polymorphic loci at a large scale and to infer past demography and the effect of evolutionary forces operation on human populations in effective ways. One such example of application of human population genetics to the study of human population genetics to the study of human evolution is support for “out of Africa” hypothesis, suggesting that modern humans evolved in Africa and moved to Asia and Europe about 100,000 years ago (Cann et al., 1987; Vigilant et al., 1991).

Population genetics has also expanded its quest to understand the basis for genetic variation in susceptibility or resistance to disease and drug’s responses. In recent years, new technologies and methodologies have been developed specifically to explore the role of genetic variation in health and disease. Proper understanding of human genetic variation is essential for the correct interpretation of the link between genetic variation and disease thereby its identification can assist in the development of diagnostic tests as well as effective treatments.

3.1 Evolutionary forces shaping genetic variation

Evolution in a broader aspect can be defined as encompassing changes over time. In the context of evolution, existence of genetic variation becomes immensely important as they form the substrate for evolution. The key forces that shape the pattern of genetic variation are Mutation, Recombination, Genetic Drift, natural Selection, Assortative mating and Migration. This section presents a brief overview of each of the aforementioned evolutionary forces.

3.1.1 Mutation

Mutation is the random change in the actual genetic code, including changes in single DNA bases, insertion or deletion of DNA sequences, and other rearrangements of DNA sequences(John, 2012).Differing by the number of bases affected, mechanism of mutation, and regions of localization these variants exist as single nucleotide polymorphisms (SNPs), insertion and deletion (InDel), short tandem repeats (STRs), variable number tandem repeats (VNTRs), copy number variations (CNVs), inversion and translocations. Mutation is the primary source of variation and has a significant impact in the process of evolution. The mutants that are found in less than 1% of a population are called variations. A polymorphic locus is defined by the presence of the most common allele in equal to or less than 99% of the chromosomes (Nei, 1987).

3.1.2 Genetic Drift

Genetic drift is a stochastic process in which a subset of a population undergoes mating that result in allele frequency variation in the next generation. At the level of an entire population, this means that each generation may not have the exact same set of allele frequencies as the previous generation (Relethford, 2012). Drift increases with the reduction in the size of the population and causes changes in allele and genotype frequencies over time. Either of the alleles is eliminated or is fixed as equilibrium is reached, but it is difficult to predict the identity of this allele due to the stochastic nature of the process. Wright (1931) proposed a model to explain the sampling in populations that leads to drift. The model assumes a finite population with a constant size and non-overlapping generations where all individuals are equally fit. Effective population size (Ne) is the number of individuals of an idealized population breeding among themselves and will have the same amount of variation in allele frequencies as the latter under drift. Ne can be used forthe comparison of genetic drift among different populations. It is also different for different parts of the genome. Two population events that occur due to genetic drift in populations that had a small size in the past are population bottlenecks (reduction in size and diversity of a single previously larger population) and founder effect (genetic separation and subsequent colonization of a subset of the total diversity of a source population).

3.1.3 Natural selection

Natural selection is Charles Darwin’s contribution to evolutionary theory, referring to differential survival and reproduction. It occurs when there is a difference in fitness (the probability of surviving and reproducing) for different genotypes, such that there is a change in allele frequency overtime. The change in color of peppered moths in England is an example of natural selection. Natural selection acts upon phenotypic variation to bring about the difference in reproductive ability of individuals with different genotypes. The rate of evolution by natural selection is proportional to the genetic variation in fitness (Fisher, 1930). The viability, mate selection, fertility and fecundity together constitute the fitness of a genotype and its relative fitness in comparison to other genotypes is given by a selection coefficient, s. When a mutation leads to a less fit genotype, it is subjected to negative or purifying selection while one which increases fitness undergoes positive or diversifying selection. When a mutant allele occurs in a diploid locus and increases the fitness of the heterozygote over homozygotes, the homozygotes are subjected to different degrees of selective pressures due to difference in individual fitness. Over-dominant selection is seen resulting in a balanced polymorphism. Frequency-dependent selection also leads to a balanced polymorphism where low frequency allele has more fitness or high frequencyallele has less fitness. Detection of positive selection signals has been done by studying candidate genes with a known function and genome wide scanning approaches (Kreitman, 2000). The signals of selection are differentiated from those of demographic events by their occurrence on selected regions of the genome in comparison to demographic events that affect the entire genome (Harris and Meyer, 2006).

3.1.4 Gene flow or migration

Migration is the inter-region movement of people and causes gene flow when migrants contribute to the next generation in the new location. Gene flow balances out genetic differentiation and lessens allele frequency differences between populations. Several population geneticists have proposed models to explain change in gene frequencies caused by gene flow mediated by migration. The “Island Model” proposed by Wright (1931) is the simplest model that shows a meta-population divides into smaller population islands of equal size which exchange genes at the same rate per generation. The “Stepping Stone Model” (Kimura and Weiss, 1964) added that genetic exchange is higher in geographically proximate populations. Another model that has gained prominence is the “Isolation by Distance” model which was based on the fact that mating choice is limited by distance and showed that increasing geographical distance decreases gene flow.

3.1.5Recombination

Genetic recombination is the exchange of segments of homologous chromosomes during meiosis. It leads to an increase in genetic diversity due to formation of new allelic combinations. Alleles in closely spaced loci do not undergo random segregation during meiosis as a result of infrequent recombination. This is why evolutionary force acting on one locus might affect adjoining loci. Two genomic events have been observed in relation to this phenomenon (i) hitchhiking results when positive selection at a locus leads to rise in frequency of another allele and (ii) selective sweep occurs due to reduced genetic diversity at loci linked to a recently fixed allele. Specific regions in different chromosomes called recombination hotspots have been reported to have higher rates ofrecombination. This shows a non-uniform distribution of recombination rates over the entire genome.

3.1.5 Non-random mating or Assortative mating

Individuals in populations do not always follow random mating patterns. Assortative mating occurs because of more or less frequent mating among specific individuals than expected in a random mating population. The genetic contribution to variance in polygenic traits is increased due to Assortative mating (Wright, 1921). Preferred mating partners can have more similar (positive Assortative mating) or dissimilar (negative Assortative mating) phenotypes than expected in random mating. Phenotypically similar individuals might have similar genotypes which are observed in consanguineous mating resulting in inbreeding. Assortative mating is however not the same as inbreeding as the former is among phenotypically similar individuals, while inbreeding occurs between individuals with similar genotypes.

3.2 A short history of population genetics

The initial development of the field of population genetics took place well outside the field of Anthropology. Although the ideas proposed by Darwin and Mendel had respective advocates, they remained incompatible for a very long time. The ideas were synthesized to explain the genetic transmission of natural selection for evolution mathematically byRonald Fisher (1890-1962), J. B. S. Haldane (1892-1964), and Sewall Wright (1889-1988). Much of the core of population genetics can be traced back to these three men in the early parts of the twentieth century. Over time, their mathematical formulations were combined with observations from laboratory experiments, field studies, and the fossil record to develop what is often referred to as the synthetic theory of evolution, referring to the synthesis of information from a variety of biological and geological fields (Provine, 1971).

Ronald A. Fisher was an English statistician, evolutionary biologist, mathematician, geneticist and eugenicist. He developed some of the concepts that have perpetual relevance to the field of population genetics. To name a few, balanced polymorphism and heterozygote advantage, ANOVA and maximum likelihood (ML) estimation of linkage. He showed how correlation between relatives can be explained by cumulative effect of a large number of Mendelian factors each having a small effect. Subsequently he devised the analysis of variance (ANOVA) which enabled disproportionate of variance to elucidate the contribution of the factors. The other major contributions were the fundamental theory of natural selection, ideas on sexual selection, inclusive fitness and parental expenditure. This piece of work established that natural selection driven evolution is primarily a within species phenomenon.

Sewall Wright:-Wright was an American geneticist. He pioneered the now standard tools of population genetics, inbreeding coefficient and F statistics. He gave the concept of the Sewall Wright effect. He also propagated the interplay of genetic drift with other evolutionary forces for adaptation to occur. For this, he devised the method of path analysis and used path coefficients to describe the outcomes of inbreeding, Assortative mating and selection (Wright, 1921). In 1931 came his seminal paper about and titled Evolution in Mendelian Populations which established that undergoing a series of maladaptive changes precedes higher levels of adaptation. Genetic drift would result in small populations. In case of a larger population undergoing sub-division into smaller units of populations, some of the latter will be better adapted. Gene flow between the smaller populations can lead to a uniform distribution of these adaptations.

J. B. S. Haldane:- Haldane was a British naturalized Indian Scientist, Well known for his work in physiology, genetics and evolutionary biology. He wrote a series of papers on A Mathematical Theory of Natural and Artificial Selection (1924-1934) and the book The Causes of Evolution (1932). His research was important for his stress upon the quantification of the rates of change of a population’s characteristics and he introduced quantitative approaches for estimating human linkage maps using a maximum likelihood method and mutation rates. He assessed the interaction of mutation and migration with natural selection for the first time. He substantiated his studies on selection by considering inbreeding, overlapping generations, incomplete dominance, isolation, migration and fluctuations of intensity of selection (Provine, 1971). He laid more emphasis on strong selection of single genes, migration and epistasis in contrast to Fisher.

There were however academic differences between Fisher, Haldane and Wright but these differences only went on to improve the subject owing to the remarkable compatibility in their overall approach. The most conspicuous difference was the three’s opinions on natural selection being the most important factor in shaping of the genetic structure of a population. Fisher and Haldane, being ardent Darwinians, were pro while Wright believed that chance factors and migration did contribute to genetic variation. Wright also laid a lot more emphasis on epistatic interactions between genes than Fisher or Haldane.

In spite of having answers on adaptive changes in populations the questions on origin of biodiversity were still unsolved. Naturalists who were meanwhile studying geographic variations within species knew the role of geographical isolation in the origin of biodiversity and eventual formation of species. However the population geneticists were unaware of these findings. The findings on the origin of biodiversity by naturalists and population genetics of adaptive changes provided the basis for the “Evolutionary Synthesis” also called modern synthetic theory of evolution (Dobzhansky, 1937). One of the most profound outcomes of this synthesis was identification of Mendelian population that comprises individuals interbreeding among themselves and sharing a common gene pool, a spatio-temporal identity and undergoing evolutionary changes (Dobzhansky, 1950). The modern synthetic theory was supported by works of Ernst Mayr, Julian Huxley and Bernhard Rensch(Meyer, 2005). The only conflicting idea in the synthesis was whether it was the gene or the individual that was undergoing selection. It was suggested that a gene can impart properties to the individual that would subsequently favor its selection (Sober, 1993).

3.3 Mathematical Models of population genetics

The foundation for population genetics was laid in 1908, when G.H. Hardy, an English mathematician and Weinberg, a German physician independently published their work which later became famous as Hardy-Weinberg equilibrium. The Hardy-Weinberg principle (Hardy, 1908; Weinberg, 1908) enabled estimation of genotype frequencies of the succeeding generations given the allele frequencies in the parental generation of a population. The law had assumptions for this population which are (i) it should be random mating, (ii) large in size; and should not be under (iii)mutation, (iv) selection, and (v)migration that could result in changes in allele frequencies. The mathematical expression for the law is as follows:

If a locus has two alleles A and a with frequencies p and q respectively, the relationship with the genotypes of the succeeding generation designated as AA, Aa and Aa is given by,

AA = p2, Aa = 2pq, Aa = q2

If the genotype frequencies in the succeeding generation have identical values to those in the parental generation, the population is said to be at Hardy-Weinberg equilibrium for that locus. In contrast, if Hardy-Weinberg is not observed, then evolution is occurring via one of the processes causing change in allele frequencies. Figure 1 shows the Hardy-Weinberg proportions for two alleles: the horizontal axis shows the two allele frequencies p and q. The vertical axis shows the expected genotype frequencies. Each line shows one of the three possible genotypes.

Figure 1: Hardy-Weinberg proportions for two alleles: the horizontal axis shows the two allele frequencies p and q. The vertical axis shows the expected genotype frequencies. Each line shows one of the three possible genotypes.

Even in the pre-molecular genetics era, the population geneticists gave theories that continue to be relevant. But, the demonstration that nucleic acids are the genetic material (Avery, MacLeod and McCarty, 1944) and discovery of double helical structure of DNA (Watson and Crick, 1953) increased the molecular geneticist’s ability to generate huge amount of molecular data. A chunk of molecular data was data on polymorphisms that characterize the diversity within populations. The models proposed by Fisher, Haldane and Wright, however, could not account for the enormity of the polymorphic data. An explanation was given by Kimura (1985) when he proposed the neutral theory of molecular evolution. The theory explains that the changes in allele frequency are a result of the random and neutral (implying no change in fitness) process of genetic drift and not the different types of selection. The theory is regarded as the null model of molecular evolution. Polymorphisms will ultimately be fixed or eliminated when they are dictated by genetic drift. The deleterious alleles might undergo negative selection but positive selection and balancing selection rarely occur. The theory also explains the constant rate of nucleotides and amino acid substitution in lineages over time. This realization forms the basis for the molecular clock hypothesis that is utilized to time evolutionary events.

Extensive datasets on DNA variation provided another major impetus to the field of molecular population genetics with the introduction of a retrospective model to learn about history. The DNA data was utilized to study the past events like events of inbreeding, gene flow or natural selection. The coalescent theory was proposed to reconstruct the ancestral state of a population(s) starting from its current state (Kingman, 1982). The theory was based on the idea that all genes in a population are derived from a common ancestral gene which is called the most recent common ancestor (MRCA) and the time to coalescence as time to most recent common ancestor (TMRCA).

The field of population genetics has earned its critics in spite of its relevance in contemporary biology. For instance, Lewontin (1980) opined that the field had a limited impact on evolutionary biologists. The models of population genetics also faced criticism for having limited application in studying polygenic traits, its avoidance of embryological development and evolutionary biology (Carroll, 2005).

Summary

By considering the broader field of genetics, Population genetics can be known as the study of heredity in organisms. It is the branch of biology that provides deepest understanding of how evolutionary changes occur. It can also refers to the study of gene and genotype frequency and predicting the way these frequencies change or remain constant under the combined influence of various factors, over time, within and between populations. Population geneticists usually focus their attention on a Mendelian population, which is a group of interbreeding, sexually reproducing individuals that share a common gene pool. Population genetics are able to apply the theory of population genetics to address a wide variety of questions about human variation and evolution by studying genetic change overtime and its effects on genetic variation within and between populations. Evolution in a broader aspect can be defined as encompassing changes over time. In this context, existence of genetic variation becomes immensely important as they form the substrate for evolution. The key evolutionary forces that shape the pattern of genetic variation are Mutation, Assortative mating, Recombination, Genetic Drift, natural Selection and Migration. Theories of evolution were given by the works ofJean-Baptiste Lamarck.Charles Darwin, Charles Lyell, Gregor Johann Mendel. Although the ideas proposed by Darwin and Mendel had respective advocates, they remained incompatible for a very long time. The ideas were synthesized to explain the genetic transmission of natural selection for evolution mathematically byRonald Fisher (1890-1962), J. B. S. Haldane (1892-1964), and Sewall Wright (1889-1988). Much of the core of population genetics can be traced back to these three men in the early parts of the twentieth century. The Hardy-Weinberg principle (Hardy, 1908; Weinberg, 1908) enabled estimation of genotype frequencies of the succeeding generations given the allele frequencies in the parental generation of a population.The law had assumptions for this population which are (i) it should be random mating, (ii) large in size; and should not be under (iii)mutation, (iv) selection, and (v) migration that could result in changes in allele frequencies. The mathematical expression for the law is as follows:

If a locus has two alleles A and a with frequencies p and q respectively, the relationship with the genotypes of the succeeding generation designated as AA, Aa and Aa is given by,

AA = p², Aa = 2pq, Aa = q²

Avery, O. T., MacLeod, C. M., & McCarty, M. (1944). Studies on the chemical nature of the substance inducing transformation of pneumococcal types induction of transformation by a deoxyribonucleic acid fraction isolated from pneumococcus type III. The Journal of experimental medicine, 79(2), 137-158.

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