Genetics Exam 3

What is a somatic mutation?

A mutation that occurs in the body cells during development or adulthood, and does not impact next generation

What is a germline mutation?

Mutations that occur in the cell lineage that is destined to become the gametes

A germline mutation is important in evolution because it

can be inherited by offspring

Phenylketonuria (PKU)

Germline mutation in phenylalanine hydroxylase that causes phenylalanine to be broken down into metabolites that affect myelin formation and lead to mental retardation.

• All newborns are tested for this disease, incidence rate is 1 in 8000.

A mutation that changes a codon for an amino acid into a stop codon is called a

nonsense mutation

• caused by one amino acid change

• leads to a shortened protein

• change on the protein level

A frameshift mutation is most likely caused by

the insertion or deletion of one or two nucleotides

• results in a change of the translational reading frame

• change on the protein level

Epigenetic regulation example

DNA methylation changes gene expression

DNA methylation is often associated with

silencing or reducing expression of a gene

Genomic imprinting occurs when

gene expression depends on whether the allele came from the mother or father

Anticipation means that

a trait or disorder appears at an earlier age or becomes more svere in successive generations

Mechanism of anticipation

1. Nascent strand forms a loop while copying the template DNA. This causes the same sequence to be copied over again, and causes this strand and the following replications to be expanded, while the template strand stays the same.

2. Template strand forms a loop before nascent strand copies it, making the nascent strand miss out on a sequence of DNA. This causes the nascent strand and its replications to be shorter, while the template strand remains normal.

Fragile X Syndrome

Intellectual disability (autism) caused by having too many CGG sequences.

• Normal human genome has 30 CGG repeats.

• Critical number appears to be greater than 50. (50-200ish means individual can be a ‘carrier’)

• Gets rapid accumulation with subsequent generations.

• Can reach 230 or more copies.

• Repeats only expand (increase in number) in female germline.

What is fragile X syndrome caused by?

Expansion of nascent DNA.

• Can only be given to offspring by mother’s germline.

• Combines germline mutations and female anticipation.

Post replication mismatch repair

Post-replication mismatch repair relies on a brief lag in adenine methylation by Dam methylase at GATC sites. For several minutes after replication, the DNA is hemimethylated: the original template remains methylated, while the new strand stays unmethylated. During this window, an enzyme complex identifies mismatches and targets the unmethylated strand for excision and repair. Once corrected, the new strand is finally methylated, resulting in full methylation and ending the cell's ability to distinguish between the two.

Proofreading

DNA polymerase proofreads by using its 3' to 5' exonuclease activity to fix errors. If a mismatch occurs, the polymerase stalls and shifts the nascent strand's end into a specialized hydrolysis site. The enzyme then cleaves the bond to remove the incorrect nucleotide, cutting the 3' OH and the rest of its nucleotide away from the DNA strand. This allows the correct base to be inserted and replication to resume.

The frequency of allele A in a population refers to

the proportion of all alleles at a locus that are A

Genotype frequency measures

the proportions of individuals with a particular genotype

Why are somatic mutations not inherited?

Because they are not in the germ line.

Why are mutations important?

One of the major processes that contribute to genetic variation, which provides raw materials for evolution.

• Genetic analysis would not be possible without mutations causing variation within individual genes.

• Mutations + recombination = genetic variation = evolution

Name the 2 Classes of mutations

1. Mutations affecting single base pairs of DNA

2. Mutations altering the # of copies of genes

Epigenetics is the basis of

imprinting and epigenetic inheritance

What can alter epigenetics marks?

diet, environment, and disease

What is epigenetic inheritance?

The process by which gene expression patterns are passed from a parent to their offspring without changing the actual DNA sequence, can be through DNA methylation.

• DNA methylation causes gene silencing, they cannot be expressed or used to make proteins with the methyl group attached.

• When epigenetic marks (DNA methylation) are passed down to daughter cells, they are passed down with the methylation.

What are two examples of imprinting?

IGF2 and H19

the expressed allele for Insulin like growth factor 2 (IGF2) is inherited from which parental side?

Parental side

• On the paternal side, the ICR and H19 is methylated, or turned off.

• This allows the enhancer to express IGF2

The expressed allele H19 is inherited from which parental side?

Maternal side

• On the maternal side, the ICR and H19 genes are not methylated, which causes CTCF protein to bind, which blocks the enhancer from reaching IGF2.

• The enhancer instead triggers the expression of H19.

Why is it important for each one to be inherited by one parent?

The offspring need exactly one copy to be healthy.

• If the offspring were to receive 2 copies of H19, there would be growth issues.

• If the offspring were to receive 2 copies of IGF2, there would be too much growth.

Steps required for imprinting - H19 and IGF2

• Both parents have one copy of the DNA strand from each of their parents

• The primordial germ cells have the imprints erased, methylation is gone.

• Imprints are then initiated based on parents (male = IGF2 active, female = H19 active)

• Turned into gametes, one male and one female are given to offspring, and now offspring has a copy of each DNA strand that has its respective active and silent genes.

Mutations in the imprinted genes can cause what to happen?

Lack of gene expression completely if active gene mutates to turn off.

Steps for Model of inheritance of DNA methylation

• Template DNA is methylated on both strands.

• When DNA replicates, the nascent strand is not methylated and the parental strand is, making the strand hemi-methylated.

• DNA methyltransferase adds methyl group to nascent strand, making both strands fully methylated.

Epigenetics definition

DNA methylation across generations

Epigenetics mouse example

Agouti gene encodes a protein that controls production of pigment in their hair follicles. Mutation causes ectopic expression (abnormal expression)

• wild type agouti: mix of yellow and black

• dominant mutant agouti = yellow

• inactive dominant mutation = black

Mutant mother fed controlled diet = yellow

Mutant mother fed diet with folate (methyl-donor) = black

Hardy-Weinburg Equilibrium

If population is in equilibrium, there is no evolution happening and no genetic change.

Not in equilibrium, evolution of genetics is occurring.

• P²+2PQ+Q²=1

P, Q, 2PQ, P+Q=1 meaning

• P = frequency of allele T

• Q = frequency of allele t

• 2PQ = frequency of heterozygote

• P+Q=1, at equilibrium

These equations only work for populations AT hardy weinberg equilibrium.

What does population genetics do?

Relates process of an individual’s genotype to the genetic composition of populations, and to changes in that composition over time and space.

Population genetics causes of change:

MMARGS

• Mutation

• Migration between populations

• Assortative Mating between different or similar phenotypes

• Recombination generating new combinatoins

• Genetic Drift - random sampling of gametes

• Natural Selection

Genotype Frequencies definition

observed proportions of genotypes in a population

Many genes in genotypes are what?

polymorphic - multiple alleles are present in a population or between different populations.

Allele frequencies are what?

the frequency of a specific allele in a population

If the frequency of a is 0.4, what is the probability of aa?

0.4²=0.16

If the frequency of a is 0.4, what is the probability of getting Aa?

• a = 0.4

• a + A = 1

• 0.4 + 0.6 = 1

• 2PQ = 2×0.6×0.4 = 0.48

Hardy Weinburg info

• Sexual reproduction maintains constant genetic variation from generation to generation.

• Unless there are events that drive the frequency of a given gene out of equilibrium.

Hardy Weinburg Multiple alleles

F(A1) = 0.5

F(A2) = 0.3

F(A3) = 0.2

F(A1/A1) = 0.5²=0.25

F(A1/A2) = 2PQ, 2×0.5×0.3=0.3

The measure of genetic variation is the amount of ______ for a gene in a population.

Heterozygosity = total frequency of heterozygotes

Bottleneck

An event that drastically reduces the size of a population. This event is random, meaning the individuals that survive do so by luck, not because they were the "fittest" or strongest.

Ex: natural disasters, german amish example

Differences between populations is due to the ________ population.

founder

Inbreeding

mating between individuals with common ancestry

Positive assortative mating

mating between individuals with similar phenotypes (race, height)

• either inbreeding or this will lead to an increase in homozygosity above the level predicted by the hardy weinburg equilibrium

German Amish example

• 17 million in germany, 200 traveled here

• bottleneck - population decreased drastically by chance

• inbreeding occurs

Frequency of Ellis-van Creveld allele

• 0.04 in the isolated population

• 0.002 in germany population

Homozygosity increases in the isolated population

Human Ancestry Geographic Map

• Neanderthal = Europe/left

• Middle = Denisovan

• Neanderthal = East Asia/right

Papuan population has the most Denisovan DNA

Introgression from Neandertals

• Circadian rhythm

• Innate immune response to viral infections

Introgression from Denisovan

• EPAS1 gene allele - responds to low oxygen levels

• Same in tibetans and denisovans

• Regulates genes responsible for O2 to tissues + hemoglobin genes

haplotype definition

A haplotype is a physical grouping of genomic variants (alleles) that are located on a single chromosome and are inherited together as a unit.

Summary of Dog Evolution

• Is reticulate - branches in and out of populations

• Dogs did not descend from current wolves, had a common ancestor but not similar currently.

• Ancient dogs are genetically distinct from present-day wolves

• Dog ancestry includes components related to more than one wolf-related source.

• Gene flow occured both before and after domestication.

• Local wolf admixture can make some dog populations appear more “wolf-life”

• Modern breeds are recent and cannot be treated as direct windows into initial domestication.