THE ORIGIN OF GENETIC VARIATION

MUTATIONS
Changes in DNA
The "raw material" of evolution

Weismann's doctrine: Sequestration of the germ plasm

Germline mutations: Important for evolution

Somatic mutations - usually short-lived effect


SUMMARY OF MAIN POINTS ABOUT MUTATION 
IN RELATION TO EVOLUTION

1. Mutations of chromosomes or genes are alterations 
that are subsequently replicated.  

They ordinarily do not constitute new species, but rather variant chromosomes 
or genes (alleles, haplotypes) within a species.

Illustrate this point with A Short History of the Concept of Mutation

Evolution of the meaning of 'mutation,' 

17th C - mutation meant any drastic change in organismal form - fossil record. 

Early in the 20th C Dutch botanist Hugo DeVries proposed a new meaning 

 DeVries thought he had solved the problem of the origin of new species
He found discretely different, true breeding forms in the evening primroses 
(Oenothera lamarckiana)  He called them new species. 

.To DeVries. Darwin's theory of natural selection became superfluous, 
because the mutation process created new species in a single step, in which 
natural selection and the environment played no role.

The slight, continuous hereditary variations in characteristics such as size and 
shape were considered by the "mutationists' to have an entirely different genetic 
basis from discrete mutations, and to play no role in evolution. 

(Later found that the 'mutations' of DeVries were mostly rare recombinations 
of several genes, produced in a plant with a very unusual system of 
chromosomes.)

Thomas Hunt Morgan discovered newly arisen aberrations, such as white-
eyed flies in Drosophila, that obeyed Mendelian rules of inheritance.

Thus mutation came to mean not necessarily the origin of a new species, but a 
spontaneous alteration of a gene. 

(However, Morgan continued to affirm that new species arise by mutation, and 
that natural selection plays no causal role in evolution.)

Now we know that a mutation is almost always an  alteration of a single gene, 
rather than a new species. 

Because mutations are relatively rare another force is required to increase the 
frequency of mutations in a population.

This emphasis on evolution as a population-level process rather than the origin 
of species as mutant individuals, is the foundation of the Evolutionary 
Synthesis of the 1930s and 1940s

 Mutation and natural selection are complementary rather than mutually 
exclusive ingredients of evolution.

Later understood that continuous variation is based on multiple genes that are 
inherited in the same way as discrete Mendelian factors. 

The mutational process generates:
a. mutations with small phenotypic effects: the basis of continuous variation
b. mutations with large effects that generate discrete variations. 
c. a continuum of effects from very small to quite large.

1950s The molecular nature of the gene elucidated 
Mutation recognized as an alteration of the base pair sequence of a gene, 
including those that have no effect whatever on the phenotype 


 2.At the molecular level, mutations of genes include 

a. Point mutations 
	Nucleotide substitutions - transitions and transversions
	Frameshift mutations
	Synonymous and nonsynonymous mutations
	3rd codon position vs 1st or 2nd position

b. Intragenic recombination

c. Deletions and insertions
	Transposable genetic elements

d. Gross chromosomal changes (karyotypic changes)
	
Intragenic recombination also gives rise to new DNA 
sequences (haplotypes).

3. The rate at which any particular mutation arises is 
quite low

on average about 10-6 to 10-5 per gamete for mutations detected by their 
phenotypic effects, and about 10-9 per base pair.  

The mutation rate, by itself, is too low to cause substantial changes of allele 
frequencies.  However, the total input of genetic variation by mutation, for 
the genome as a whole or for individual polygenic characters, is appreciable.

4. Phenotypic effects of mutation - may be small or great.

The magnitude of change in morphological or physical features 
caused by a mutation can range from none to drastic. 
	Mutations are limited to pre-existing traits
 	Mutations alter preexisting biochemical or developmental pathways, so not 
	all conceivable mutational changes are possible.  Some adaptive changes may 
	not be possible. 

The rate and direction of evolution may sometimes be affected by the 
availability of mutations.

 5. Fitness effects of mutations - range from lethal to neutral 
	The average effect of mutations on fitness is deleterious, 
	but  some mutations are advantageous.  

Mutations with large effects are often deleterious, but some believe that such 
mutations have sometimes been important in evolution (e.g., Goldshmidt's 
"hopeful monsters"			Insert Fig. 10.8.

 6. Mutations are random in the sense that:
a. Their probability of occurrence is not directed by the environment in 
favorable directions 
b. Specific mutations cannot be predicted.  
c. The likelihood that a mutation will occur does not depend on whether 
or not it would be advantageous.

7.Recombination as a source of variation
Recombination of alleles can potentially give rise to astronomical numbers 
of gene combinations, and in sexual organisms generates far more genetic 
variation per generation than mutation alone.  
	
	Erosion of variation by recombination
	recombination also breaks apart favorable gene combinations, and constrains 
	the amount of variation displayed by poly-genic characters.

 8. Mutations of the karyotype include: 
		polyploidy (which can  give rise to new species) 
		rearrangements that alter chromosome number or arrangement of 
	genes.  Many such rearrangements reduce fertility in the heterozygous 
	condition.

 9.Unequal crossing over causes deletions and duplications of genes 

	This is one of the processes responsible for gene families and increases in 
genome size and gene number.

 10. Genetic variation in most populations is augmented by gene flow .
In some cases, genes acquired by hybridization with closely related species 
add genetic variety.  Examples are known of horizontal gene transfer 
between very distantly related organisms particularly in bacteria.

POPULATION STRUCTURE AND GENETIC DRIFT

Unlike ideal populations, in Hardy Weinberg equilibrium, real 
populations are often structured and of finite size

Mating is therefore not at random, and allele frequencies 
fluctuate by chance sampling - GENETIC DRIFT

ADAPTATIONS do not result from genetic drift

COALESCENT THEORY
See Figure 11.2 in Futuyma

Assumes no selection, no mutation, finite population size

Can be applied to a lineage of asexual organisms in haploid 
populations 
OR to individual genes in a sexually-reproducing population

With increasing time, more and more lineages go extinct

Therefore the average degree of relationship among individuals 
increases with time

Eventually, all copies, at time t, are 
descended from a single ancestral copy
i.e., the geneology of all genes coalesces to a single common 
ancestor
     
e.g., Either A1 or A2 becomes FIXED in the population

The population becomes MONOMORPHIC for one allele
Refer to figure 11.3 (A and B) in Futuyma

At time 0, what is the probability of fixation of 
allele A1? allele A2?

TIME TO COALESCENCE

Assume a population of constant size,
N gene copies, N haploid organisms or N/2 diploid organisms
For a diploid locus, the average time to coalescence for a pair 
of genes is 2N generations

EVOLUTION BY RANDOM GENETIC DRIFT

1. Allele frequencies fluctuate at random, but eventually one or 
another allele becomes fixed.

2.  Therefore, the population eventually loses its genetic 
variation.

3. Populations that are initially similar will diverge in allele 
frequency and may eventually become fixed for different 
alleles.

4.  The probability, at time t, that an allele will become fixed is 
equal to the frequency of the allele at that time.

5.  The smaller the population, the faster the rate that fixation 
will occur.

EFFECTIVE POPULATION SIZE (Ne)
Census size (N) is usually > than number that contribute genes
1. Variation in progeny number by either or both parents
2. Unequal numbers of males and females
3. Overlapping generations
4. Fluctuations in population size

FOUNDER EFFECTS
An interesting e.g. of a "bottle-neck", i.e., a severe restriction in population 
size due to a small number of founders


INBREEDING 

AUTOZYGOSITY: identity by descent of two alleles.

The degree of inbreeding is measured by F, 
the coefficient of inbreeding

Probability that an individual taken at random 
from a population, will be autozygous = F 
 will be allozygous = (1-F)

Inbreeding redistributes alleles from the 
heterozygous to the homozygous state

F = 0 in a population that is not inbred
F = 1 in a fully inbred population

Example of a pedigree - insert

GENETIC CONSEQUENCES OF INBREEDING

1. Genotype frequencies are changed (relative to Hardy 
Weinberg), but allele frequencies remain the same.

2. The genetic variance of a phenotypic character within a 
population is usually increased by inbreeding.

3. Inbreeding depression reduces the mean of a phenotypic 
character (usually one affecting fitness) due to the increased 
frequency of homozygous recessive phenotypes.

4. Inbreeding can promote linkage disequilibrium, i.e., non 
random associations of alleles at different loci (this is 
because it reduces the frequency of heterozygotes and 
therefore the opportunity for recombination).