4. modes of inheritance I

Species

group of organisms comprised of similar individuals capable of interbreeding

Population

individuals of a particular species occupying a definite space, in which individuals interact, interbreed, and exchange genetic material

Gene pool

all alleles from all individuals within a population

Allele/ genotype frequency

proportion of individuals in a population with a specific allele/ genotype

may differ among populations

Population genetics

Quantitative study of the distribution of allele frequencies in a population and its changes over time and between populations

Mathematical modeling of allele behavior offers insight into the genetic susceptibility to disease

Hardy-Weinberg law

Allele frequencies remain constant over time in a population that does NOT evolve = genetic equilibrium

allele frequency calculations

factors that disturb hardy weinberg equilibrium

1. Non-random mating

2. Small population size

3. Mutations 

4. Natural selection

5. Immigration and emigration

Small population size

random effects (survival, fertility), unrelated to carrying the mutant allele, can
change allele frequency between generations

Mutations

new alleles introduced in the gene pool

Natural selection

predilection for a positive allele → disruption of equilibrium

Immigration and emigration

addition or removal of alleles

Non-random mating

Increased frequency with which carriers mate → substantial deviation from equilibrium

Stratification

population with subgroups that remained genetically separate

If that subgroup has an allele with higher frequency than of that the whole groups → apparent excess of homozygotes in the overall population

No effect on frequency of autosomal dominant disease

Assortative mating

Choice of mate based on a particular trait

Long-term effect is minor

Consanguinity and inbreeding

Recessive disorders in offspring of related parents are rare and unusual

(eg. Tay-Sachs disease in the Ashkenazi Jew population 1:3600 vs. 1:360000 in general population)

Mutations and selection

Occur very slowly and in small increments inducing small deviations from the HW equilibrium

Most detrimental recessive alleles are hidden in heterozygotes

selection has no short-term effect

Fitness (f)

measure of surviving affected offspring compared to control (outcome of collaboration between survival and fertility)

Main factor that determines whether a mutation is lost, becomes stable, or even becomes dominant in time

f=1 means

a mutant allele is as likely as the wild-type to appear in the next generation

f=0 means

the allele causes death or sterility or is negatively selected against

Stable allele frequency

balance between removal (selection) and addition (mutations) of mutant alleles to a gene pool

Gene flow

slow diffusion of genes through barriers

Involves large populations and slow change in allele frequency

Genes of migrant populations are slowly merging in the gene pool of
the population they migrate into (similar neighboring populations)

ex. DCCR5 mutation – highest frequency in Europe, small in Middle
East and India and almost absent in Africa

Ethnic differences in allele frequency

Until recently, humans lived in isolated groups = larger differences in allele frequency between populations

Factors that influence differences in alleles and allele frequency among ethnic groups

genetic drift and heterozygote advantage

Genetic drift

random change in allele frequency in small populations due to chance

Individuals with the mutant allele may have more offspring (by chance) → allele becomes frequent in population in time

founder effect & bottleneck event

Founder effect

genetic drift after a few individuals (a fraction of the pool) start a new population in isolation from original population (different frequencies)

Bottleneck effect

genetic drift after event that drastically reduces population size (might have different allele and genotype frequencies)

Heterozygote advantage

when heterozygotes have increased fitness over wild-type homozygotes

Increased frequency of mutant allele

ex. Sickle cell anemia and malaria

Changes in selective pressure → change in frequencies

Single-gene disorders (mendelian)

Determined primarily by alleles on a single locus

Follow primarily one of the classical inheritance patterns (autosomal dominant/recessive, X-linked dominant/ recessive)

OMIM – approx. 8000 single-gene disease or traits
in humans

Pleiotropy 

a single abnormal gene → a variety of phenotypes in different organs, with different signs and symptoms, at different times

Penetrance

probability that a mutant alleles will have a phenotypic expression (all-or-none)

If a genotype fails to express = reduced/incomplete penetrance

Age-dependent for some disorders

Expressivity

degree of phenotype severity

variable expressivity

Severity of symptoms is different in individuals with same genotype

pedigrees

Graphical representation with standard symbols of a family tree to establish the pattern of transmission

proband (propositus/a or index case)

First individual diagnosed with disease in a family

how to interpret pedigrees: 1. Autosomal vs. sex-linked

Mostly males → likely X-linked

50:50 M:F → autosomal

Male-to-male transmission → autosomal

how to interpret pedigrees:  2. Dominant vs. recessive

One parent must have the disorder → dominant (2 affected parents can have an unaffected child)

Neither parent must have it → recessive (2 unaffected parents can have an affected child)

Autosomal dominant inheritance (AD)

Only one copy of a diseased allele is required for the possibility to exhibit the phenotype

Quite rare, but >50% of all mendelian disorders

Eg. Huntington’s disease, polycystic kidney disease, familial hypercholesterolemia

characteristics of AD

No skipping generations - each individual has at least one affected parent (unless it is a new mutation)

The recurrence risk for each child of an affected heterozygote parent is 50%

A significant proportion of cases are sporadic, due to de novo mutations

Both sexes display the phenotype in equal ratios and are as likely to transmit it to their offspring

Normal siblings of affected individuals are not carriers of the disease

Defective gene product is usually a structural protein, transcription factor

Autosomal recessive inheritance (AR)

Phenotype exhibited only when both alleles are mutated

Eg. albinism, phenylketonuria, alkaptonuria, sickle cell anemia, cystic fibrosis

Characteristics of AR

Males and females are equally affected

The recurrence risk for the offspring of 2 heterozygotes is 25%; if a homozygote mates with a heterozygote, the recurrence risk is 50%

Multiple siblings in the same generation manifest the trait (not in parents or offspring)

Parents of affected individuals are generally asymptomatic carriers and in some cases may be related (skips generations)

Products of affected genes are mostly enzymes

Y-linked inheritance

Very few genes (Y-specific related to spermatogenesis or primary determination and some housekeeping with X- homologs)

Transmitted strictly from father to son in all generations

Affects ONLY males

X-linked inheritance

Easy to distinguish from autosomal inheritance

Possible genotypes:

Male → hemizygote

Female → homo/heterozygote

X-linked recessive inheritance

X-linked loci are similar to autosomal loci for females; however, due to randomized X-inactivation, half of cells will express the normal allele and half the mutated one in heterozygotes

Eg. hemophilia A, Duchenne muscular dystrophy, colorblindness

Characteristics of X-linked recessive 

Higher incidence in males than females

Heterozygous females generally unaffected

Trait skips generations

Mutant allele never transmitted from father to son!

All daughters of affected fathers are carriers!

X-linked dominant inheritance

Very few disorders and less prevalent

Expressed even in heterozygotes (affects both females and males), similar to autosomal dominant

Characteristics of X-linked dominant inheritance

Distinguished from autosomal dominant by lack of male-to-male transmission

Affected males with normal mates → no affected sons and no normal daughters

Affected females mating with normal males produce ½ sons and ½ daughters affected

Males have usually a more severe phenotype (might be lethal)

Affected females are twice as common as affected males