G&H Week 8 Lecture Notes PDF

GENETICS & HEALTH WEEK 8 Population genetics & Evolution Lecture Dr Craig McFarlane WEEK 8 LEARNING OUTCOMES By the end of this week you should be able to: § Appreciate that allele frequencies in a given population are influenced by factors such as: non-random mating; natural selection; migratio...

GENETICS & HEALTH WEEK 8 Population genetics & Evolution Lecture Dr Craig McFarlane WEEK 8 LEARNING OUTCOMES By the end of this week you should be able to: § Appreciate that allele frequencies in a given population are influenced by factors such as: non-random mating; natural selection; migration and genetic drift. § Apply the Hardy-Weinberg Equation to a population with allele frequencies in equilibrium. § Understand that allele frequencies change over time. § Recognize that evolution is a process in which natural selection drives changes in a specific populations genetic variation; and that over time, this results in phenotypic change. KEY POINTS § EVOLUTION is a process in which GENETIC VARIATION in a population changes over time. § NATURAL SELECTION is the driving force of EVOLUTION. § DARWIN'S four POSTULATES of natural selection. § ALLELE frequencies in populations DO NOT reflect MENDELIAN RATIOS. § HARDY-WEINBERG discovered the relationship between ALLELE frequencies and GENOTYPE frequencies: p2 + 2pq + q2 = 1 § The Hardy-Weinberg equilibrium is only maintained under certain conditions. § Random genetic drift, founder effect, mutation-selection balance, heterozygote advantage and migration all affect population genetics. THE THEORY OF NATURAL SELECTION The idea of evolution - had existed for a 100 years before Darwin. Problem was how?, what drove evolution? Charles Darwin postulated a mechanism (natural selection) and backed up his ideas with examples he had collected during his travels. The Theory of Natural Selection is based on four basic ‘postulates’ 1. Individuals within a population vary from one another. 2. Much of the variation between individuals is heritable. 3. Organisms tend to produce more offspring than the environment can support, and inevitably many will die. 4. Individuals with some characteristics survive and reproduce better than do individuals with other characteristics. NATURAL SELECTION Main inferences drawn from Darwin’s observations: § Inference 1: Production of more individuals than can survive leads to a struggle for existence. Very few offspring survive to reproduce. § Inference 2: Survival in the struggle for existence is not totally random, depends on inherited traits. Individuals best suited to their environment are likely to survive and leave offspring. § Inference 3: Unequal ability to survive and reproduce leads to gradual change in populations. Favourable traits accumulate over many generations. KEY DIMENSIONS OF DARWIN’S THOUGHT 1.Species change. Darwin found bones of related, but distinct earlier forms. 2.Populations are ever increasing, so survival NOT guaranteed. Evidence of extinct animals in the fossil record. 3.Species varied from place to place. e.g. Australia, with isolated species: Koala & kangaroo. 4.Variation emerged over time; species had deep relations & shared origins, over thousands to millions of years. Skeleton of Toxodon in Buenos Aires 1.6 mya - 16 kya Darwin was one of the first to collect Toxodon fossils. Darwin paid 18 pence for a T. platensis skull from a farmer in Uruguay. FINCHES OF THE GALAPAGOS ISLANDS § Darwin visited the Galapagos Islands during his voyage. § Noted 13 species of Galapagos Is. finch and one Cocos Is. finch. § Observed that beak size and shape correlated well with diet. § Size and shape of the beak has an important consequence for their “reproductive fitness” § Whether or not they could reproduce and have offspring. § Noted that living species had distinct resemblance to fossil species. § And each island had its own unique fauna. § Impt: Organisms on different islands were different, but had similarities to one another, and similarities to mainland South American species. § Still the same species. POPULATION DISTRIBUTIONS - TRAITS 1 SD Are the traits exhibited by organisms fit- for-purpose? • E.g. Beak size/shape and food source. • Can influence reproductive fitness. 2 SD 3 SD NATURAL SELECTION With natural selection: § Species have significant inherited variation. § More individuals are born than can survive to reproduce. § Variation affects reproductive success (reproductive fitness). § Over time, species adapt to ecological niches (environment). Nature proposes Selection disposes e.g. Mutations, Variations. e.g. Deleterious mutations removed. EVOLUTION BY NATURAL SELECTION NUMBER OF INDIVIDUALS REPRODUCTIVE FITNESS • The majority of individuals in a population will show the common phenotype (what has adapted over time) and this will follow a normal distribution. PHENOTYPE PHENOTYPE Reproductive fitness: reflects the ability of individuals to pass on their genes to subsequent generations. EVOLUTION BY NATURAL SELECTION NUMBER OF INDIVIDUALS Reduced reproductive fitness PHENOTYPE PHENOTYPE NUMBER OF INDIVIDUALS REPRODUCTIVE FITNESS • What happens when reproductive fitness changes? PHENOTYPE EVOLUTION BY NATURAL SELECTION NUMBER OF INDIVIDUALS REPRODUCTIVE FITNESS Increased reproductive fitness PHENOTYPE NUMBER OF INDIVIDUALS PHENOTYPE PHENOTYPE NATURAL SELECTION EXAMPLE: PEPPERED MOTH: BISTON BETULARIA Before the industrial revolution. § Species of night flying moth with speckled grey wings: Before After § Habitat: Lichen covered tree trunks. § Coloration made them difficult to see. § Consequence of industrial revolution (trees became darker): § 1849 First melanics reported near Manchester, England. § 1886 Less than 2% were light colored. Remaining were melanics. § Hypothesis: “Industrial melanism” due to natural selection. Rare Rare Alleles with greater fitness increased in population. EVOLUTION BY NATURAL SELECTION PEPPERED MOTH: BISTON BETULARIA NUMBER OF INDIVIDUALS REPRODUCTIVE FITNESS PRE-INDUSTRIAL REVOLUTION (speckled) PHENOTYPE MOTH COLOUR (Black) NUMBER OF INDIVIDUALS REPRODUCTIVE FITNESS INDUSTRIAL REVOLUTION (soot & pollution) (Black) PHENOTYPE (speckled) MOTH COLOUR EVOLUTION BY NATURAL SELECTION PEPPERED MOTH: BISTON BETULARIA NUMBER OF INDIVIDUALS REPRODUCTIVE FITNESS PRE-INDUSTRIAL REVOLUTION (speckled) MOTH COLOUR NUMBER OF INDIVIDUALS INDUSTRIAL REVOLUTION (soot & pollution) REPRODUCTIVE FITNESS PHENOTYPE PHENOTYPE (Black) (speckled) (Black) MOTH COLOUR http://faculty.ircc.edu/faculty/tfischer/images/limiting%20drug%20resistance.jpg EXAMPLE: ANTIBIOTIC RESISTANCE: POPULATION PERSPECTIVE § Modern medical-relevant example of natural selection. § Differential sensitivity to antibiotics within a bacterial population. § If course of antibiotics not completed then population of highly resistant bacteria can remain and take over. EXAMPLE OF EVOLUTION AND NATURAL SELECTION: - ANTIBIOTIC RESISTANCE https://www.youtube.com/watch?v=plVk4NVIUh8 Fossil record Comparative Anatomy - Tetrapods Although different, similarities exist. Glyptodon vs. Armadillo Similarities btw extinct and present-day animals. Primitive Reptiles Mammal-like Reptile Selective Breeding Lemur Human EVIDENCE OF EVOLUTION Molecular era - Phylogenetics Sequence comparison. Identify highly conserved regions of genes & proteins btw species. Vestigial organs EVOLUTION & NATURAL SELECTION Evolution key points: 1. Mutations occur extremely frequently. 2. Mutation results in variability in traits of a species. 3. Natural selection is common in wild populations. 4. Species can evolve quickly in response to natural selection. 5. Fossil record suggests these processes have been occurring for a long time (e.g. Glyptodon). 6. We need to remember that the earth is BILLIONS of years old. (we have only been on it for a relatively short period of time). THEORY OF NATURAL SELECTION SO: § In every generation (in natural populations) only a select few individuals will survive long enough to reproduce. § Those that do, will pass on their genes to the next generation. § The chance of survival is not totally random - those individuals with certain characteristics - like the ability to avoid predators will be more likely to reproduce. § This means that characteristics that favour survival and reproduction tend to be the traits that are passed on to the next generation. § Over time, with new heritable variation arising, and certain traits selected for each generation, organisms will tend to evolve features that favour their survival & reproductive success in the current environment. THE REDISCOVERY OF MENDEL’S LAWS § Darwin was unable to explain how variation between individuals originated or how particular variants are inherited. § After Mendel’s work was appreciated in early 1900s, it became obvious how traits exhibiting a selective advantage could be inherited. § Genetic variation originates when one allele mutates into another allele. Occurs frequently – SNPs & GWAS. § Through natural selection - mutations that impair survival and/or reduce reproductive success; reduce in frequency within a population. § Mutations conferring increased survival and/or improved reproductive success, increase in frequency within a population. § Mutations that are neither ‘better’ or ‘worse’ than any other allele are considered selectively neutral. Neutral traits may drift in frequency by random chance. POPULATION GENETICS & EVOLUTION § Evolution is a process in which genetic variation in a population changes over time… § Population Genetics is the study of how these variations change under the influence of… § Systematic forces (e.g. selection) § Random forces (e.g. genetic drift) § Therefore, the discipline of population genetics is predominantly concerned with changes in Allele Frequencies. Figure 15.16, Lewis, 11/e DOMINANT & RECESSIVE ALLELES Q: If dominant traits are usually good then why don’t dominant alleles take over a population and recessive alleles become lost over time? A: Because selection has a role and selection occurs at the level of the Phenotype and not the Genotype. § At the level of the individual (in a population), we refer to them as either Homozygous or Heterozygous for alleles at a particular locus. § If we consider populations of individuals, we can combine & measure the number of heterozygotes (1 copy of each allele) & homozygotes (2 copies of the same alleles). § From this we can then calculate the frequency of gene alleles in the entire population. IN 1908: HARDY AND WEINBERG MATHEMATICALLY DESCRIBED THE RELATIONSHIP BETWEEN ALLELE FREQUENCIES AND GENOTYPE FREQUENCIES 2 Types of eggs in a population “p”= frequency of dominant allele (T) “q”= frequency of recessive allele (t) in a population T t Tt (pq) T TT (p2) tt (q2) Tt (pq) t 2 Types of sperm in a population TT : Tt : tt p2 : 2pq : q2 GENOTYPE FREQUENCY This is called the HARDY-WEINBERG principle, which forms the basis for HARDY-WEINBERG equilibrium HARDY-WEINBERG 5 CONDITIONS Hardy & Weinberg argued that if 5 conditions are met, allele and genotype frequencies will remain constant from generation to generation in a population (in-equilibrium). § The breeding population is large Reduces the problem of genetic drift. § Mating is random No particular mating preference. § There is no mutation of the alleles Alleles don’t change. § No migration change No immigration or emigration. § There is no selection All genotypes have an equal chance of surviving and reproducing. When these 5 conditions are met then HARDY-WEINBERG equilibrium is said to be met. WHEN IN EQUILIBRIUM When the 5 key assumptions underlying the Hardy-Weinberg principle are met, you can calculate the relative frequency of the different genotypes in a population according to the equation: p2 + 2pq + q2 = 1 Where: p = frequency of one allele (dominant) q = frequency of the other allele (recessive) (and therefore: p + q = 1) For two alleles at a single locus in a population, the genotype frequencies are given by the expansion of the binomial expression: (p+q)2 = (p2 + 2pq + q2) = 1 For three alleles at a single locus, the genotype frequencies are given by expansion of the trinomial expression: (p+q+r)2 = p2 + 2pq + 2pr + 2qr + q2 + r2 = 1 APPLICATIONS OF HARDY-WEINBERG Consider the following genotype frequencies at the M-N blood type locus: (M-N blood group system in humans is different from ABO and was discovered after the ABO system. The MN blood group in humans is under the control of co-dominant alleles LM and LN). BLOOD TYPE M MN N GENOTYPE LM LM LM LN LN LN NUMBER OF PEOPLE 1787 3039 1303 6129 § Total number of alleles is 2x (1787 + 3039 + 1303) = 12258 § Total number of LM alleles is 2x (1787) + 3039 = 6613 § Frequency of the LM allele is 6613/12258 = 0.5395 § Total number of LN alleles is 2x (1303) + 3039 = 5645 § Frequency of the LN allele is 5645/12258 = 0.4605 § Because LM and LN are the only two alleles of this gene, Frequency of the LM + frequency of the LN = 1 (0.5395) p + (0.4605) + q =1 =1 APPLICATIONS OF HARDY-WEINBERG § So, we have now calculated the frequencies of the LM and LN alleles in our population and have confirmed they add up to 1. § Now, we need to calculate the frequencies of genotypes in our population. § For this we use the expanded formula - p2 + 2pq + q2 APPLICATIONS OF HARDY-WEINBERG So far we have just calculated allele frequencies. If the assumptions of the Hardy Weinberg Equation apply to this population (no selection, yes random mating, yes large population, etc.) then the genotypic ratios in the next generation should be: LMLM LMLN LNLN p2 2pq q2 (0.5395)2 2(0.5395 x 0.4605) (0.4605)2 0.2911 0.4969 0.2121 BLOOD TYPE M MN N GENOTYPE LM LM LM LN LN LN No. OF PEOPLE (OBSERVED) 1787 3039 1303 No. people expected if pop is in HWE EXPECTED 1784 3046 1300 e.g. LMLM 0.2911 x 6129 (total people) = 1784 If the population size remains static, and we compare these predictions (expected) to the original data sample (observed), we can conclude that: This population is in H-W Equilibrium at this locus. To confirm, we use the Chi-square test (GLS). HARDY-WEINBERG EQUILIBRIUM § With random mating and no survival advantage or reproductive differences between genotypes, the allele frequencies created at fertilization will be preserved in the next generation. § Also if population is large, the allele frequencies will remain unaltered, generation after generation. § This condition is referred to as: Hardy-Weinberg Equilibrium APPLICATIONS OF HARDY-WEINBERG § Hardy-Weinberg equation is useful for estimating the genotype frequencies from allele frequencies in human populations. § Consider the autosomal recessive metabolic disorder PKU. § Approximately 1/10,000 people are affected. § Therefore, Homozygous affected frequency = 0.0001 (q2) § The frequency of all disease alleles in the population = q And we know q2 = 0.0001, therefore q = √0.0001 = 0.01 and as p + q = 1, p = 0.99 § So, we would expect that the frequency of heterozygous carriers of a defective PKU allele to be: (freq ‘pq’ genotype) = 2pq = 2 x 0.99 x 0.01 = 0.02 or 1 in 50 HARDY-WEINBERG EQUILIBRIUM Males are unique, they are Hemizygous X-linked male p+q=1 No heterozygote state We use this formula for both allele and genotype frequencies in males with X-linked conditions p2 + 2pq + q2 = 1 Autosomal recessive Autosomal dominant X-linked female All have a heterozygote state H-W: AS IT APPLIES TO FEMALES § In a large randomly mating population, approximately 1 in 8,900 males are affected by an X-linked recessive disease. § What percentage of women in that same population would you expect to be carriers for this disease? p+q=1 p2 + 2pq + q2 = 1 p + 1/8,900 = 1 8,899 + 1 = 1 8,900 8,900 p + q = 1 0.9999 + 0.0001 = 1 p + q = 1 Female carriers = 2pq 2 x 0.9999 x 0.0001 = 0.0002, which equates to 0.02% or 1.8. or 2 8,900 HARDY-WEINBERG: AUTOSOMAL RECESSIVE § In a large randomly mating European population, approximately 1 in 1600 individuals are affected by a autosomal recessive disease. § What percentage of individuals in this same population would you expect to be carriers of this disease? p2 + 2pq + q2 = 1 q2 = 1/1600 q = √1/1600 = 1/40 p = 39/40 We want to calculate 2pq portion of formula p + q = 1 or 0.975 + 0.025 = 1 2 x 0.975 x 0.025 = 0.049 Carriers of this disease = 2pq About 1 in 20 (5%) EXCEPTIONS TO HARDY-WEINBERG There are many reasons that H-W will not be applicable to all populations - the major ones include: 1. 2. 3. 4. 5. Non-random mating Unequal Survival Mutation Population Subdivision Migration All shift a population out of equilibrium Modification of the H-W equation to account for these circumstances are (luckily) beyond the scope of this course - nevertheless their consequences need to be appreciated. 1. NON-RANDOM MATING § In human populations, individuals are oblivious to the genotype of their mate for the vast majority of genetic loci. § Thus for most genes, alleles combine at random. § However, some phenotypic traits are often a major influence when choosing a mate: e.g. hair colour, skin colour, intelligence & altruistic traits (generosity, selfless, helps others). § This type of non-random mating is called: Assortative Mating. § Some cultures also favour marriage involving related individuals. § This type of non-random mating is called: Consanguineous Mating. 2. UNEQUAL SURVIVAL Aa x Aa A a Aa a aa ♀ A AA Two copies of the dominant allele causes lethality. Thus, HardyWeinberg Equilibrium (HWE) will never be met. Aa aa : Aa : AA 1 : 2 :1 Tall : short: (Lethal) 1 : 2 : (1) GENOTYPIC RATIO PHENOTYPIC RATIO 2. UNEQUAL SURVIVAL § If zygotes, produced by random mating have different survival rates (depended on their phenotype), H-W equilibrium will not be maintained. § Unequal survival is the driving force for natural selection § This can manifest through: § Selective disadvantage (eg. Albinism, homozygous aa genotype lacks pigmentation/white moth on black trees) § Selective advantage (eg. Aa heterozygote is more reproductively “fit” than either AA or aa). § Both, in which case deleterious alleles can be maintained at high frequencies in a population. CONCEPT: HETEROZYGOTE ADVANTAGE § Any allele severely deleterious in the homozygous state would be expected to be slowly lost from the gene pool. § However, if the heterozygous carrier is at a mild selective advantage over the homozygous normal, then that allele may be maintained in a population - sometimes at a surprisingly high frequency. M 0.8 a la ria 1.0 0 Relative Reproductive Fitness Heterozygotes have the highest reproductive fitness, as such, will persist in population. MUTATION-SELECTION BALANCE § Sometimes deleterious alleles can be maintained in a population (where there is no heterozygote advantage) by a dynamic equilibrium. § In this case, the deleterious allele is being lost from the population (through natural selection) at the same rate that it is being regained by spontaneous mutation. Introduction of a mutation, (a), at rate = µ Population Elimination of allele a by selection (s) at rate = s x q2 3. MUTATION § Mutation leads to a change in allele frequencies and shifts a population out of equilibrium. For example: § Consider a population where: ‘A’ = p= 0.6 and ‘a’ = q = 0.4 § And suppose that the ‘A’ allele mutates to ‘a’ at a a rate µ of 1 x 10-5. § Then ‘A’ will decrease by 0.6 x 1 x 10-5 = 0.000006 § & ’a’ will increase by the same amount § Thus, the new allele frequencies will be: § p=0.599994 and q=0.400006 4. POPULATION SUBDIVISION § H-W applies when a population is a random interbreeding group. § When anyone can mate with anyone else: Panmictic. § Reality! Populations are often subdivided by geographical, ecological or cultural barriers. § These subdivisions make populations inhomogeneous. § Surveys may indicate that an allele is not in H-W equilibrium, but - if each sub-population is considered separately, an allele may be maintained in equilibrium. CONCEPT: FOUNDER EFFECT § When a small sub-population becomes isolated (culturally or geographically), non-random sampling of the original population can produce a special type of genetic drift - called Founder Effect. § Small founder populations have a much reduced level of genetic diversity compared to the original population. § Certain deleterious alleles, through the action of the Founder Effect, can reach high frequencies in this way. Main Population c = 0.01 Founder effect, Non-random sample becomes reproductively isolated. c = 0.2 New Population CONCEPT: FOUNDER EFFECT § When a small sub-population becomes isolated (culturally or geographically), non-random sampling of the original population can produce a special type of genetic drift - called Founder Effect. § Small founder populations have a much reduced level of genetic diversity compared to the original population. 9 sailors & 18 native Tahitian islanders HMS Bounty route § Certain deleterious alleles, through the action of the Founder Effect, can reach high frequencies in this way. 2012: only 50 inhabitants remain (UK Daily Mail) CONCEPT: BOTTLENECK EVENT § A sharp reduction in population due to: earthquakes, floods/droughts, fires, disease or genocide. § Genetic diversity remains lower, only slowly increasing with time as random mutations occur. § Toba catastrophe theory (1990s) that a bottleneck of the human pop’ occurred c.70,000 ya. § Human population reduced to ~10,000 people by Toba supervolcano erupted. CONCEPT: RANDOM GENETIC DRIFT § With small numbers, the stochastic nature of Mendelian segregation leads to random drifting of population allele frequencies. Cc Cc § Consider a mating of Cc parents that produce 2 children. § The two options that maintain the little c = 0.5, is most likely, the chance that the frequency of c will go up or down is 10/16 - greater than the chance it will remain static. § If population size is small, alleles can be readily lost by random genetic drift. Starting Frequency of c = 0.5 Freq of c in next generation ?? FREQ c 0 0.25 Genotypes CC, CC CC, Cc 0.5 cc, CC Cc, Cc 0.75 1.0 Cc, cc cc, cc ?? Probability of combination 1/16 4 / 16 6 / 16 4 / 16 1/16 5. MIGRATION § When individuals move from one territory to another, they bring their genes with them. § If the allele frequencies differ between the populations, and immigration is continuous, then H-W equilibrium will be continually disrupted. § However, if immigration stops, and all the other requirements of H-W are met, within one generation H-W equilibrium will be restored. POPULATION c=0.5 Migration allele frequencies are changed in the population POPULATION POPULATION NOW HAS STARTS WITH c=0.1 Allele frequency for c will not be maintained in equilibrium. GLS § Population questions – lots of them. SS § Muddiest points from the GLS