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Summary Evolutionary developmental biology
Evolutionary Developmental Biology notes directly from the lectures and course material, integration with laboratory practicals and workgroups.
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EVOLUTIONARY DEVELOPMENTAL BIOLOGYIt is surprising that Darwin’s assumption, that natural selection acts upon spontaneously and
randomly emerging hereditary changes, turned out to be largely correct, even when his
principle of natural selection was consolidated with an adequate theory of genetics only in
the course of the twentieth century.
The experiments with plants conducted by geneticists, Mendel, and biologists at first seemed
to be in conflict with the Darwinian idea that evolution works through natural selection in
response to small differences between individuals. Hugo de Vries observed that evening
primrose, when crossbred, could undergo substantial phenotypic changes, which he
attributed to ‘mutations’. This interpretation was – in hindsight – not correct, because the
phenotypic changes were in fact caused by a deviating system of chromosome pairing and
recombination, specific to evening primrose. Based on his observations, De Vries stated that
evolution proceeds in leaps. He described the emergence of new plant species as a
consequence of mutations, while Darwin had claimed that evolution works through natural
selection on small differences within the species. Thus, a difference of opinion arose
between biologists who claimed that mutations were the driving force behind evolution
(mutationists) and people who stated that natural selection was the driving force
(selectionists). The discrepancy between mutationism and selectionism was solved between
1920 and 1940, with the ‘Modern Synthesis’, a theory of evolution that combined heredity
and natural selection. Major changes of body form occur within short evolutionary time
windows and that such punctuational change, alternated by long periods of stasis or
undirected fluctuation, dominates the history of life. Phyletic gradualism, i.e. continuous
small changes within an evolutionary lineage guided by directional selection, would be rare.
The concept of punctuated equilibria does not necessarily imply evolution by
macro-mutations, it just acknowledges the fact that the intensity of selection, and
consequently the rate of evolution changes over time.
HERITABLE MUTATIONS - The emergence of variation: Evolution makes use of genetic
variation, and variation emerges through mutation. Mutations are spontaneous changes in
the DNA, caused by errors during DNA replication, defects during meiotic recombination,
unequal crossing-over, gene conversion, the action of mobile elements, imperfections during
repair of strand breaks, and environmental influences, such as UV radiation and reactive
chemicals. Human genomes are 99.9% identical, differing at 3.3 million nucleotides. In the
human genome 44.7% of the sequence is due to transposable elements, such as DNA
transposons, LTR long terminal repeat retrotransposons, SINEs and LINEs. This situation as
such is not uniquely human, as mammalian genomes on the average contain 50%
transposons and remnants of transposons, while plants contain even much more. The
human genome is particularly rich (1.1 million copies) in so called Alu-elements, which are
SINEs. The mutations caused by transposition are not always destructive; they are often
neutral and sometimes may be a source of novelty.
The first type of locus is called hypervariable. These are pieces of DNA that mutate so
quickly that everybody has his or her own variant. In forensic science these markers are
used to associate DNA traces with a suspect. Right across are loci that barely change over
many generations (conservative genes). The difference is in the evolutionary pressure on
the locus: a mutation that causes loss of function in a gene that is of crucial importance for
survival is quickly eliminated, for example, because the fetus is not viable. If mutations are
unidirectional, that is, if an allele A mutates into an allele a without ever mutating back, then,
given enough time, the original allele A will disappear from the population.
,Then if we designate the forward mutation rate by u and the backwards mutation rate by v,
the frequencies of the two alleles will reach an equilibrium (‘mutational equilibrium’), which is
given by: qeq=u / (u+v), where qeq is the equilibrium frequency of allele a. This shows that
when the two mutation rates are equal, the equilibrium frequencies of a and A will both
become 0.5, and when v is small compared to u, qeq will approach unity. The rate at which
allele frequencies reach mutational equilibrium is usually quite slow; it may take several
thousands of generations, so it is usually not considered an important factor in human
populations.
SNPs: the most common mutation in the human genome is a substitution of one nucleotide;
this leads to ‘single nucleotide polymorphisms. The human genome has an estimated 10
million of such variable positions, most of them in noncoding stretches of the genome and
are selectively neutral. If they are in the open reading frame of a functional gene, phenotypic
consequences may occur, especially in the case of a non-synonymous substitution
(synonymous is third base changes, redundancy). As SNPs can be found throughout the
genome and the genomic environment of most SNPs is known, they are excellently suitable
in genetic mapping studies, correlated with disease profiles and are used as markers for the
genomic position. An example of a medically relevant SNP is a polymorphism in the LDL
receptor: a protein that is anchored in the cell membrane and is able to bind lipoproteins
from the blood, after which these are incorporated in the cell via endocytosis. There are
several SNPs in the gene encoding the LDL receptor; one of them is called the ‘J.D.
mutation, which involves a triplet TAT that is mutated to TGT, as a result of which amino acid
828 of the protein has changed from tyrosine to cysteine. The mutated protein does not
settle in the membrane, the cell is unable to bind LDL from the blood, the cholesterol content
of the blood becomes chronically high, eventually leading to an increased risk of
cardiovascular diseases.
Microsatellites: also called STR (Short Tandem Repeats) or SSR (Simple Sequence
Repeats), or VNRTs (Variable Number of tandem repeats), a microsatellite is characterized
by a core sequence and a repeat number and a mutation could, for instance, consist of a
change from five to six repeats, usually due to DNA polymerase losing contact with the DNA
strand during DNA replication, and subsequently continuing in a ‘wrong’, meaning shifted,
position. VNTRs are used when information about the coding genes are not available.
Microsatellites can reside in coding DNA sections or in non-coding DNA. If they are in coding
DNA, it will always concern a core sequence of three base pairs, or a multiple of three. An
example of a VNTR in a coding DNA is the polymorphism in dopamine receptor D4, a protein
is anchored in the cell membrane of a neuron and on the outside has a binding site for the
neurohormone dopamine. DRD4 thus ensures that the neuron reacts to dopamine, and one
of f the intracellular loops of the protein contains a VNTR that consists of a core sequence of
48 bases, In most people this is repeated about four times (this is called the 4R allele), but a
variety of repeats, from two to eleven times, occur, in varying frequencies. The 7R allele is
special: it is associated with certain behavioral phenotypes, such as explorative behavior,
ADHD and self-transcendence. As 7R occurs at a relatively high frequency, there must have
been positive selection on it, which could be the case if the phenotype with increased
explorative behavior had an advantage.
Indels: insertions and deletions, such mutations could concern a short sequence or a
relatively long one, and the short indels are caused by errors during DNA replication, the
long ones due to recombination and unequal crossing-over during meiosis. Indels form an
important source of differences between humans and chimpanzees. any pieces of DNA,
whether in human beings or in chimpanzees, are inserted or deleted, resulting in a large
,number of differences (not included in the truism that humans and chimpanzee are 98.5%
identical in terms of their DNA), so according to Britton, this percentage should rather be
95% when all indels are taken into account.
Duplications, inversions, translocations and loss of genes: Gene duplication and gene loss
are important mutation symptoms that are especially essential in the evolution of species.
Quite often we find that evolutionary lineages after splitting from their ancestor are subject to
expansions or reductions in the number of genes in a gene family, most likely as a result of
adaptation to new conditions.
Chromosome mutations: inversions, fusions, duplications and translocations, and many of
them have medical relevance as they are associated with large phenotypic consequences
(trisomy 21 and Robertsonian translocation). A chromosome mutation that might have been
important for the evolution of the hominins is the fusion between two ape chromosomes,
leading to our chromosome 2. All apes have 23 autosomes, and we have 22. Recent
research on the genome of Denisova Man shows that also this species had the chromosome
fusion. This is evident from the position of a repeated TTAGGG motive, characteristic for
telomeres. For the Neanderthal genome this has not yet been sorted out properly as the
available genome sequences are not as good as the Denisova genome, but it’s very likely
that Neanderthal had 22 autosomes, too, given the cross-breedings between humans,
Neanderthals and Denisovans. Usually when two related species differ in the number of
chromosomes the production of fertile offspring by the hybrid becomes a problem, as a
synaptic pairing of chromosomes during meiosis is prevented. A relatively common
chromosome mutation in humans is a pericentric inversion in chromosome 9, common for
1-3% of humans, and this should cause loss of chromosomal material due to their inability to
properly form a synaptic pair during meiosis, but no phenotypic consequence is shown.
POPULATION GENETICS: - Equilibrium between allele and genotypes
Mutation leads to new alleles, of which the frequency changes as a result of selection or
drift, hence the definition of evolution according to the Modern Synthesis. But selection
operates on the phenotype rather than on an allele.
Allele frequency is defined as the number of alleles of a specific type in a population, relative
to the total number of all alleles at a particular locus, the latter equalling two times the
number of individuals if every member of the population is diploid.
The easiest assumption is that the allele and genotype frequencies are in equilibrium,
meaning that every allele in the population randomly combines with another allele to form a
genotype; consequently, the genotype frequencies are completely determined by the allele
frequencies.
Hardy-Weinberg rule: If, in the case of a locus with two alleles, A and a, the allele
frequencies equal p and q, the frequencies of the three genotypes AA, aa, and Aa will equal
p2 , q2 and 2pq, respectively. Using the Hardy-Weinberg principle, the expected genotype
frequencies can be calculated if the allele frequencies are available. If the observed
genotype frequencies are also available, one can test whether the population is in
Hardy-Weinberg equilibrium. As indicated, the principle of Hardy and Weinberg applies if the
alleles of a locus randomly combine into genotypes, and the biological terms are:
- a large population;
- no selection;
- no mutations;
- no migrations;
, - there is panmixia: the chance for an individual to breed with another individual is
equal for every individual.
The HW equilibrium formulates a null hypothesis for almost all population genetic studies:
the rule expresses what we ‘normally’ would expect. Despite the very stringent conditions
listed above it appears that the principle holds widely in field populations including human
populations, even when the principles are not entirely followed.
According to the Hardy-Weinberg equilibrium, genotype frequencies are quadratic functions
of allele frequencies. The frequency of heterozygotes is always maximal if the two allele
frequencies are equal (p = q = 0.5). If one of the allele frequencies is small the frequency of
homozygotes becomes very small, much smaller than that of the heterozygotes. This
principle underlies the common observation that disease alleles in a human population
almost only occur in the heterozygotes who do not express the disease. Only few people are
actually ill (the homozygotes), whereas a much larger part of the population is a ‘carrier’ (the
heterozygotes). Conversely: if selection acts against an adverse allele, it may take a long
time before it is removed from the population, because selection only affects the
homozygous recessives. If there is selection the Hardy-Weinberg equilibrium of course
doesn’t apply. Usually this is noticed on the basis of too few homozygous recessives, and it
is actually only noticed when the homozygous recessive is lethal (population 3).
The degree of selection is quantitatively expressed as the selection coefficient s, the relative
decrease of a certain genotype under the influence of selection in one generation. The
opposite is the ‘fitness’ of that genotype, a term that leads back to Darwin, which obviously
depends on the combination of genotype and environment.
The relationship between fitness and selection is: W = 1 – s, and if in a population a
genotype ( AA) produces 100 fertile offspring and another genotype (aa) 90, selection
against aa is said to equal s = 0.1, while the fitness of aa equals W = 0.9. In population
genetics fitness is always regarded relative to the genotype in the same generation that has
the highest number of offspring or the best survival; this is given the value 1. In the event of
complete dominance only the homozygous-recessive genotype is selected against, so the
recessive allele will only slowly disappear from the population. If selection is against the
dominant allele, this allele, depending on the degree of selection, will quickly disappear from
the population. Co-dominance occurs if both alleles are expressed in the heterozygote, The
heterozygote has a phenotype that is distinct from the homozygous dominant and can be
recognised as such in the population, and in this case selection against a recessive allele
influences the allele frequencies more quickly than in the case of regular dominance. Finally,
overdominance occurs when the heterozygote has a higher fitness than both homozygotes;
the consequence is an overrepresentation of heterozygous genotypes in the population. This
type of heredity leads to retention of genetic variation: as both alleles provide an advantage,
they are both maintained and the population remains polymorphic. An example of
heterozygote advantage is the human MHC II, a collection of co-dominant genes that codes
for proteins involved in the immune system. So, it is advantageous to be heterozygous, as
this provides a better protection against infectious diseases. The result is that human
populations are often very polymorphic for these genes. If selection is against both
homozygotes, allele frequencies will decrease if they are high, whereas allele frequencies
will increase if they are low (because the allele is then largely present in the heterozygotes,
which are favored). The result is that allele frequencies reach equilibrium, somewhere in the
middle, where the increase flips over to a decrease: qeq= s / (s+t), where s and t are the
selection coefficient against both homozygous genotypes.
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