Lecture 4: Genotypic and Phenotypic Variation
Contents
Lecture 4: Genotypic and Phenotypic Variation¶
Mutation and Variation¶
Mutation is the ultimate source of variation. Without variation there could be no evolution, so mutations are of great importance to evolution. Important to point out that existing variation can be reshuffled by a variety of mechanisms such as crossing over, and that we don’t always consider these in quite the same way as mutations leading to increases or decreases in variation and thus altering the potential for evolution. That said we can revisit this when we consider additive genetic variation for a trait.
Mutation = a heritable change. This is often followed by the qualifier “in the DNA” or “in the genetic material”. This is redundant with the term “heritable” but points out an important genetic issue: The mutations which are of primary concern are those in the germ line as these are the one that will be passed on. August Weismann was the first to point out the distinction between germ and soma. Mutations in your arm or knee cap are not going to get passed on because the germline is sequestered relatively early in development.
Weismann’s doctrine was a serious blow to Lamarkian inheritance of acquired characteristics. However, in plants and some animals (clonal ones in particular) the germline is not sequestered into a single part of the part of the organism, and instead somatic mutations can be inherited. For instance a mutation during the differentiation of a branch on which a flower will develop will be carried in pollen and ovules made by that flower. Thus they will have a genotype different from the rest of the plant. This sort of mixed soma/germline is present in other organisms as well such as corals.
Probably one of the most important things to understand about evolution is that mutation is random, i.e., is not directed towards the problems presented by the environment (although on more than one occasion in the literature their have been challenges to this assumption: Lenski, R. E. Are some mutations directed? 1989.
Mutation is an ongoing process. There are measurable mutation rates and there can be a genetic variation for mutation rates; for instance “mutator strains” of bacteria exist. At a mechanistic level consider mutations in the replication or repair machinery of DNA that may alter mutation rates.
Types of mutation: point mutation now generally refers to a change at a single nucleotide site. These can be transitions (purine to purine [A to G or G to A], or pyrimidine to pyrimidine [C to T or T to C]) or transversions (from a purine to a pyrimidine or vice versa). Synonymous and non-synonymous substitutions with respect to the effect on the amino acid coded for by the DNA. Deletions and insertion will cause frameshift mutations.
Transposable elements are mobile genetic elements that can move from one part of the genome to another. Generally they have repeated sequences at their ends and code for protein(s) in the middle. In moving from one location to another they can cause mutations. If the element landed in the middle of the coding sequence of a gene, it most likely would lead to a frameshift mutation or introduce a stop codon, and knock out the function of that gene. See this fun review for more information.
Gene duplications can occur by unequal crossing over where gene families exist on the chromosome, homologous chromosomes may misalign and cross over (recombine). The daughter chromosomes include one with an extra copy and one with one fewer copies. Chromosome rearrangements can also be viewed as mutations. Classic cases: inversions were a section of the chromosome is inverted with respect to the “normal” chromosome. Drosophila polytene chromosomes show characteristic banding patterns and allow for easy recognition of inversions. A paradigm of natural selection (more later).
Several important consequences: Inversions can act as suppressors of crossing over in the heterokaryotype (= heterozygote for two different chromosomal types). An inversion does not prevent crossing over per se but the recombination products that result from a crossover within the inversion either have two centromeres and are pulled apart in division, or lack a centromere and are not transmitted. Only the parental-type (non-recombinant) chromosomes are transmitted.
How will the frequency of an inverted chromosome in a population affect its role as a suppressor of recombination? The more frequent the inverted type gets, it will be present in a “homokaryotypic” state and recombination will not be suppressed. If the “inverted” chromosome were fixed in the population (=100%) then we would no longer consider it “inverted”.
Translocations are instances where part of a chromosome is “translocated” = moved to another chromosome. When entire chromosome arms are translocated or fused this can lead to changes in chromosome number. Can also lead to genetic incompatibilities that may lead to reproductive isolation (more in lectures on speciation).
Phenotype and Genotype¶
Definitions: phenotype is the constellation of observable traits; genotype is the genetic endowment of the individual. Phenotype = genotype + environmental influences on development. To consider these in the context of evolutionary biology, we want to know how these two are related. In a narrow “genetic” sense, the genotype defines the phenotype. But how, in and evolutionary sense, does the phenotype “determine” the genotype? Selection acts on phenotypes because differential reproduction and survivorship depend on phenotype. If the phenotype affecting reproduction or survivorship is genetically based, then selection can winnow out genotypes indirectly by winnowing out phenotypes.
How do we get from genotype to phenotype? Can think about this like Central dogma, but of course we should expect exceptions: DNA via transcription to RNA via translation to protein; proteins can act to alter the patterns and timing of gene expression which can lead to cell-type differentiation where cells take on different states; cell communication can lead to pattern formation and morphogenesis and eventually we have an adult!
Genotype is also used to refer to the pair of alleles present at a single locus. With alleles \(A_1\) and \(A_2\) there are three possible genotypes \(A_1A_1\), \(A_1A_2\) and \(A_2A_2\). With three alleles \(A_1\), \(A_2\), \(A_3\) there are six possible genotypes: \(A_1A_1\), \(A_1A_2\), \(A_1A_3\), \(A_2A_2\), \(A_2A_3\), \(A_3A_3\). First we must appreciate that genes do not act in isolation. The genome in which a genotype is found can affect the expression of that genotype, and the environment can affect the phenotype.
Not all pairs of alleles will have the same phenotype: dominance when the phenotype of \(A_1A_1 = A_1A_2\), \(A_1\) is dominant, \(A_2\) is recessive. An allele can be dominant over one allele but recessive to another allele. Model of dominance from enzyme activity: no copies produce no phenotype, one copy produces \(x\) amount of product and two copies produces \(2x\) then the alleles are additive and there is no dominance (intermediate inheritance). If one copy of the allele produces as much product (or has as high a rate of flux) as a homozygote then there is dominance. There are cases where the heterozygote is greater in phenotypic value than either homozygote called overdominance, or the logical opposite underdominance.
Single genes do not always work as simply as indicated by a dominance and recessive relationship. Other genes can affect the phenotypic expression of a given gene. One example is epistasis (literally “standing on”) where one locus can mask the expression of another. Classic example is a synthetic pathway of a pigment. Mutations at loci controlling the early steps in the pathway (gene 1) can be epistatic on the expression of genes later in the pathway (gene 3) by failing to produce pigment precursors (e.g. albinos) A\(\rightarrow\)gene 1 \(\rightarrow\) B \(\rightarrow\) gene 2 \(\rightarrow\) C gene 3 \(\rightarrow\) Pigment
Genes are said to pleitropic if they affect more than one trait. The single base pair mutation that lead to sickle cell anemia is a classic example. The altered hemoglobin sequence is not the only effect: lower oxygen affinity=anemia; clogged capillaries=circulatory problems; in heterozygote state=malarial resistance. Mutations in cartilage are another example since cartilage makes up many different structures the effects of the mutation are evident in many different phenotypic characters.
Polygenic inheritance can be explained by additive effects of many loci: if each “capital” allele contributes one increment to the phenotype. With one locus and additive effects we have three phenotypic classes: AA, Aa and aa. With two loci and two alleles in a strictly additive model (i.e., no epistasis or other modifying effects) we can have five phenotypic classes aabb\(<\)Aabb=aaBb\(<\)AaBb=AAbb=aaBB\(<\)AABb=AaBB\(<\)AABB and the intermediate phenotypic values can be produced in more ways, so should be more frequent. The more loci affecting the trait, the greater number of phenotypic classes. As the number of loci increases the phenotypic distribution will converge to the normal distribution (i.e. a bell curve)– this is a fundamental assumption of quantitative genetics (more later) and a great biological example of what is known in probability theory as the Central limit theorem.
Patterns of Variation¶
Evolution by Natural Selection rests on the following principles:\
there is variation in natural populations
the variation is heritable; has a genetic basis
more offspring are produced than will survive each generation: struggle for existence
if heritable variation affects survival/reproduction, there will be differential reproduction \(\rightarrow\) selection
Without genetic variation there will be no evolution. Thus, characterizing the genetic variation in natural populations is fundamental to the study of evolution. (see The Genetic Basis of Evolutionary Change by Lewontin, 1974)
What kinds of variation are there? Discrete polymorphisms (e.g., Biston betularia) are easily noticed, but not frequent or representative of the variation in natural populations. Continuously varying traits are much more common, and we generally describe them using mathematical descriptions such as the mean \(\bar{x} = \frac{1}{n}\sum_{i=1}^{n}x_i\) and variance \(\bar{v} = \frac{1}{n-1}\sum_{i=1}^{n}(x_i-\bar{x})^2\). Examples: human height, blood pressure, milk production of a cow, oil content in corn, etc.. Continuously varying traits will have both genetic and environmental components. The study of the genetic basis/architecture of continuously varying traits is known as Quantitative Genetics. This is perhaps the single most important aspect of biology to human health and medicine today! Do you know why? If you are a premed understanding statistics will be much, much more important that understanding organic chemistry….
How much genetic variation is there? Historical debate: Classical school held that there was very little genetic variation, most individuals were homozygous for a “wild-type” allele. Rare heterozygous loci due to recurrent mutation; natural selection purges populations of their “load” of mutations. Balance school held that many loci will be heterozygous in natural populations and heterozygotes maintained by “balancing selection” (heterozygote advantage). Selection thus plays a role in maintaining variation.
How do we measure variation? To show that there is a genetic basis to a continuously varying character one can study 1) resemblance among relatives: look at the offspring of individuals from parents in different parts of the distribution; can estimate heritability (more later). 2) artificial selection: pigeons and dogs show that there is variation present in traits people have bred for.
Protein electrophoresis: phenotype = gene product of specific locus (loci). Took off in mid 60’s (Lewontin and Hubby, 1966; Harris, 1966); great historical review here. Grind up organism in buffer, apply homogenate to gel (starch, acrylamide), apply electric field, proteins migrate in gel according to charge, stain gel with histochemical stain for enzyme activity, bands reveal variation. Do this for many loci and can estimate: proportion of loci polymorphic per population (10-60%, depending on organism); proportion of loci heterozygous per individual (3-20% depending on organism). The technique provides a minimum estimate because different amino acid sequences may migrate at the same rate in the gel.
DNA variation. Measure the genetic material directly; sequencing is the most precise and used to be the most laborious; restriction enzyme analysis was faster and contained less information. In recent years, revolutionary technology has been released to allow for massive collection of DNA sequence data. All these techniques have revealed that there is even more genetic variation that what was revealed by protein electrophoresis. Hence the debate between the Classical and Balance schools of genetic variation has evolved into a debate about the forces maintaining genetic variation: the Neutralist-Selectionist controversy (or debate). Some loci are neutral; others under selection (more in lecture on Molecular Evolution). The debate is not over, and in fact your professor was recently involved in a flare up of this discussion.
How is variation apportioned within and among populations? Hierarchy in patterns of variation: are populations either melanistic or normal; or do populations contain some of both; if so what are the frequencies in different populations? Is the variation within or among populations?
Spatial Patterns of Variation
Geographical isolates: discontinuous or disjunct distribution. Is there
differentiation? Are there continuous distributions, clinal variation,
abrupt discontinuities (“step” cline).