Genetics 3200	Feb 18, 1999

When we think of evolution, most of us think of Darwin’s revolutionary
mechanism of evolutionary change: NATURAL SELECTION. Though Darwin’s
theory made a huge splash when introduced in 1859, it did not gain full
acceptance until nearly 70 years later! 

Why not? There were lots of pieces missing, such as…
	What was the genetic material? 
	How was the material inherited? 
	How was variation generated such that natural selection could
	operate? 

When these pieces came together, the fields of genetics and evolution were
revitalized after decades of nasty, unfruitful debate among academics.
This "Modern Synthesis" married the fields of population genetics,
evolution, and paleontology (blossoming in the 1930's). 

Natural Selection
How Natural Selection works:
-Say you have a gene and mutation has generated 2 allelic states of that
gene: 
A= the wild-type allele (dominant) 
a= the mutant allele (recessive). 

-Allele "a" bears a mutation which negatively impacts the function of that
particular gene and therefore the fitness of organisms carrying that
allele. 
-The "cost" of a given deleterious mutation to an organism’s fitness is
called the "selection coefficient" or "s"; this value is the decrement in
fitness (from a maximum value of 1) which is caused by a mutation. The
mutation in allele "a" bears an "s" value of 0.04 in the homozygous state. 
-Therefore, the fitness associated with the 3 genotypes for this locus
are: 
wAA= 1.0, wAa= 1.0 and waa= 0.96. 

How does natural selection deal? If aa genotypes have lower fitness, then
that individual’s which carry that genotype will contribute fewer progeny
and fewer copies of "a" alleles to subsequent generations. Over many
generations, a mutation conferring lower fitness for a given allele may be
lost (purged) due to natural selection. Allelic frequencies are expected
to change such that the frequency of allele "A" approaches or reaches 1.0
(fixation) and the frequency of allele "a" approaches 0.0 (loss).

COMPUTER DEMO:
Scenario	a) Generations=1000; waa=0.96
		b) Generations=1000; waa=0.90

SO, the greater the cost to fitness (larger s value)( the faster natural
selection weeds out alleles bearing deleterious mutations.

What about beneficial mutations? They may also arise in a population and
increase the fitness of individuals carrying those mutant alleles through
a positive selection coefficient. Over time, the mutant allele (a) may
sweep to fixation (frequency 1.0) through natural selection. 

COMPUTER DEMO:
Scenario	a) Generations=1000, waa=1.02
		b) Generations=1000; waa=1.04

Are all mutations either deleterious or beneficial? 
-NO, there’s a huge class of neutral mutations which arise along DNA
sequences without affecting the phenotype, and therefore the fitness of an
organism (s = 0). 
-Where are neutral mutations most likely to happen? "junk" DNA, introns,
3rd positions of codons in protein coding genes. 
-Alleles bearing these mutations are not subject to the forces of natural
selection, but may evolve (undergo changes in frequency) in populations
via Genetic Drift.
 
Genetic Drift
-Genetic drift is change in a population’s allelic frequencies resulting
from chance variation in the survival and/or reproductive success of
individuals. Genetic drift is a random process which, by definition, does
not discriminate among alleles as would natural selection. The result is
that any given allele is equally likely to be lost or fixed by genetic
drift as another; genetic drift is considered "nonadaptive" evolution.

Drift occurs via "sampling error" of the parental gene pool, where alleles
which comprise the next generation’s gene pool are not at contributed at
the same frequencies as in the parental generation. The greater the number
of "samplings" from a parental gene pool (i.e. the greater the number of
progeny produced in a given generation), the closer the allelic
frequencies will be to their original frequencies. Thus, population size
has a great effect on the magnitude of genetic drift. 

In fact, the rate of genetic drift= 1/2Ne, where Ne refers to the Genetic
Effective Population Size.

What is Ne and how does it relate to Genetic Drift? 
-In this course, we have only talked about population size in terms of a
census population size, BUT in population genetics, you deal more
frequently with the Genetic Effective Population Size= Ne. It is defined
as size of theorized population (wherein no selection, migration, mutation
occurs) which would lose genetic variation to drift at the same rate of
the actual population. 
-Why do we think in terms of Ne? Often, in large populations, there is
lots of variance in individual reproductive success, and not every
individual is contributing equally to the next gene pool. So genetically,
the population size is much "smaller" as the numbers of reproducing
individuals are often far less than the census population size.

In populations with large values of Ne, the effect of genetic drift is
very small (barely effects allelic frequencies over time), but in
populations with small Ne, drift is swift and allele frequencies may
change very rapidly (rapid evolution). One of the largest consequences of
swift rates of genetic drift is genetic variation is rapidly lost from a
population through the fixation of a single allele for given locus. 

COMPUTER DEMO: NO difference in fitness between genotypes
Scenario	a) Generations= 100, Ne= 500
		b) Generations= 100, Ne= 50
		c) Generations= 100, Ne= 5

C. Neutral Theory
With the advent of really good DNA sequencing technologies, lots of DNA
sequence data has been rapidly  generated in recent decades. It has been
observed that there are many allelic variations (mutations) along
closely-related DNA sequences. Under Darwinian evolution, these slight
genetic changes would be operated upon by natural selection, which would
ultimately determine their fate. 
OVERHEAD
But what a guy named Kimura noticed (1968) is that most of these genetic
changes occurred at positions that have no functional significance, such
as 3rd position changes in protein coding genes (sites "free from
selection"). He developed the Neutral Theory of Evolution which states
that most evolution which is observed at the level of DNA sequences are
neutral mutations which are evolving due to genetic drift. His theory
claims only negative natural selection plays a role in evolution, culling
mutations which are deleterious (negative s value). Neutral Theory holds
that Positive Darwinian Selection is not a prominent force in the
evolution of most genes because beneficial mutations at the level of DNA
are VERY rarely observed.

Nearly-neutral theory spurred decades-long debate about whether most
evolution occurs via genetic drift (neutralists) or through natural
selection (selectionists).

Has anyone tested Neutral Theory?
1. Hughes and Nei challenged Neutral Theory by examining the mutational
accumulation patterns at a locus influencing immune function (the antigen
recognition site of Mhc proteins). They discovered results contrary to
neutral theory in that the number of nonsynonymous changes was
significantly greater than the number of synonymous changes. What
evolutionary force would produce this kind of pattern?= Positive Darwinian
Selection acting to sweep new mutational variants to fixation MUCH faster
than could be accomplished by drift.

*There are other cool examples and tests which we may go into later when
discussing whether or not a genetic marker is truly "neutral" and the
importance of neutrality for inferring phylogenetic relationships among
taxa.

D. Nearly-neutral theory: 
Shortly after Neutral Theory was proposed, another body of theory was
developed by Ohta (1972). Her theory of nearly-neutral evolution addressed
the countering forces of genetic drift and natural selection for a special
class of mutations. We specified earlier that mutations may be
deleterious, beneficial, or neutral with respect to the fitness of an
organism, but nearly-neutral theory identifies that a large class of
deleterious mutations (those of very slight effect, with a small "s"
value) may act as neutral mutations in the gene pools of small
populations. 

The reason follows (Keep in mind): Rate of genetic drift= 1/2Ne
Selection Coefficient for a given slightly deleterious mutation= "s" 

1. If "s" for a given mutation is relatively large, such that s > 1/2Ne,
natural selection dominates the evolution of that allele and it is culled
from a population (selected against).
-Another way to express this relationship: If 2Nes > 1, then natural
selection "operates"

2. If "s" for a given mutation is very small, such that s < 1/2Ne, then
genetic drift overwhelms natural selection and the mutation is "free" from
the influence of selection. 
	If 2Nes < 1, then genetic drift dominates natural selection

*The smaller the population size, the greater the magnitude of genetic
drift and a greater number of increasingly deleterious mutations are
permitting to "slip by" natural selection. Once these mutations arise in
gene pool of a small population, they may sort as if neutral, THOUGH THEY
CARRY A COST TO FITNESS. If these mutations become fixed, then the
population’s fitness is permanently reduced by the value "s" of that
particular allelic mutation.

COMPUTER DEMO: 
Scenario	a) Generations= 1000, waa= 0.96, Ne= 500
		b) Generations= 1000, waa= 0.96, Ne= 50
		c) Generations= 1000, waa= 0.96, Ne= 5

What does this mean for populations confined to small Ne over evolutionary
time? Nearly Neutral theory predicts that small populations will
accumulate greater numbers of slightly deleterious mutations in their gene
pools than will large populations. Over time, the fitness of small
populations may erode due to the enhanced rates of deleterious mutational
accumulation, until extinction results (a "mutational meltdown"). Models
of this genetic deterioration indicate extinction may occur in as few as
several hundred generations (depending on the population size). Given that
many endangered species are now managed as populations of very small Ne,
this theory suggests that they may be increasingly vulnerable to
extinction via mutational meltdown. 

There are very few tests of Nearly-Neutral theory and NO tests of
Mutational Meltdown yet published.