Genetics 2250 topic 1

Genes

– basic units of biological information

• Segments of DNA with discrete locations

• Specify protein or RNA molecules

• Underlie heritable traits

Heredity

transmission of traits from parents to offspring

Genome

– total of all genes/genetic information

• Controls diverse array of heritable traits

• Predictable patterns

Genetics

- science of heredity

• Seeks to explain structures and mechanisms of inheritance

Heritable traits

– specific characteristics of individuals that ‘run’ in families

• Single gene (monogenic)

• Two or a few genes

• Many genes…

• … and environmental variables (nature vs nurture for things like weight)

Basic principles of genetics worked out by monk and plant breeder, __, in 1866

Gregor Mendel

Genetic laws

make testable predictions about patterns of trait inheritance

gregor mendel’s Hypothesis

- observable traits are determined by units of inheritance • (now known as genes)

Artificial selection

purposeful control of mating by choice of parents for next generation

• Domestication of plants and animals

• Key transition in civilization

• Unpredictable

Two key misconceptions about inheritance

1) • Inherited features of offspring contributed mainly by one parent

• Homunculus inside sperm (a microscopist said he could see a fetus (bro said person but nah) inside a sperm)

2) • Parental traits mixed and permanently changed in offspring

• Blended inheritance

the 6 components of mendel’s experimental approach

1. Pea plants as an experimental organism

2. Traits with clear-cut alternative forms

3. Created and crossed true-breeding lines of pea plants with alternate forms of traits

4. Reciprocal crosses

5. Quantitative

6. Brilliant and practical

1. Pea plants as an experimental organism

• Male and female reproductive organs

• Self-fertilize

• Can be cross-fertilized

• Short breeding time

• Large numbers of progeny

2. Traits with clear-cut alternative forms

• Discrete traits (vs continuous traits)

• Trace unambiguously

• Alternate forms - antagonistic pairs

antagonistic pairs

Alternate forms of the same trait

3. Created and crossed true-breeding lines of pea plants with alternate forms of traits

• Generated lines of peas that bred true for the form of a trait

• Pure-breeding or true-breeding

• Inbred lines

• Cross-fertilized true-breeding lines with alternate forms of a trait

• Hybrids - offspring of genetically dissimilar parents

Hybrids

offspring of genetically dissimilar parents

Each hybrid resembled only one parent

Dominant

form of a trait observed in the hybrid

4. Reciprocal crosses

• Reversed characteristics of male and female parents

• Controls which parent transmits a form of the trait

• Progeny of reciprocal crosses were similar

• Both parents contribute equally to inheritance

5. Quantitative

• Counted large numbers of progeny

• Analyzed results numerically

• Tested against predictions

6. Brilliant and practical

• Simplified, controllable experimental system

• Attention to detail

• Monohybrid cross

• Mating between true-breeding parents that differ in form of a single trait

• First filial generation (F1) –

progeny of parental generation

• Second filial generation (F2) –

progeny of F1

alleles

• Each gene has alternate forms - alleles

Combinations of __determine form of a trait

alleles

Monohybrids

individuals with two different alleles of a single gene

The law of segregation

the two alleles of a gene separate during gamete formation, then unite at random, one from each parent, at fertilization

(a) The two alleles for each trait separate during gamete formation. (b) Two gametes, one from each parent, unite at random at fertilization.

monohybrid mendels unlinked autosomal phenotypic ratio

3:1

Product rule

predict chance of a particular fertilization event

the probability of two independent events occurring together is the product of their individual probabilities

• What is the probability that event 1 AND

▪ P(1 and event 2 will occur? 2) = probability of event 1 X probability of event 2

Sum rule

predict proportion of progeny with an allele combination or form of a trait

– the probability of either of two mutually exclusive events occurring is the sum of their individual probabilities

• What is the probability that event 1 OR

▪ P(1 or event 2 will occur? 2) = probability of event 1 + probability of event 2

mendels linked autosomal crosses monohybrid f3 generation phenotypic ratio

2:1

Law of segregation made prediction of two types of F2 plants with dominant form of trait – hybrid and true-breeding – 2:1 ratio

Phenotype

- observable form of trait

Genotype

pair of alleles underlying phenotype

Homozygous/homozygote

having two of the same allele

• Homozygous dominant, homozygous recessive

Heterozygous/heterozygote

having two different alleles

• Phenotype of heterozygote defines dominant allele

Testcrosses:

a way to establish genotype

• If an individual has a dominant phenotype, what is their genotype?

• Testcross – cross to individual with recessive phenotype and examine progeny

• all dominant - unknown genotype is homozygote

• 1:1 ratio of dominant to recessive - unknown genotype is heterozygote

Dihybrid

heterozygous for two genes

Dihybrid cross

Cross of true-breeding parents with alternate forms of two trait

F1 dihybrids __ to give F2 progeny:

self-fertilized

Parental type

phenotype combination seen in a parent

Recombinant type

phenotype combination not seen in a parent

The law of independent assortment ratio expectencies

• If alleles segregate independently from each other into gametes expect:

• 1:1:1:1 ratio of 4 possible gametes in each dihybrid parent

• 16 equally likely fertilization outcomes (¼ X ¼ = 1/16)

• 9 genotypes in F2 progeny

• 4 phenotypes in F2 progeny

• 2 parental, 2 recombinant

• 9:3:3:1 phenotype ratio

• 3:1 phenotype ratio for each of the two traits separately

Law of independent assortment

During gamete formation, different pairs of alleles segregate independently of each other.

• Independence of segregation and subsequent random union of gametes determines phenotypes observed

• The product rule shows the 9:3:3:1 phenotype ratio mathematically

Branched-line diagrams

• Keep track of probabilities of potential outcomes in a genetic cross

• Progeny phenotypes for each gene in different columns

• Overall phenotype probabilities determined by multiplication

• Easier than Punnett’s square for phenotypes of multiple genes

Testcrosses with dihybrids

• Mate unknown genotype to individual homozygous for both recessive traits

• Different, predictable results for each possible genotype of the unknown

Multihybrid crosses

mating F1 progeny of true-breeding parents that differ in three or more traits

• Number of possible gamete genotypes from a multihybrid

• 2^#traits

• Aa Bb Cc Dd → 24 = 16 possible gametes

• Punnett square - 16 X 16 matrix with 256 outcomes

• Break down multihybrid cross into independently assorting monohybrid crosses

Recessive Alleles Are Most Often __, While Dominant Alleles Are Usually _

Nonfunctional, Functional

Genes typically encode

proteins, often enzymes

• Dominant allele often encodes _

a functional version of the protein

• Recessive allele often encodes __

nonfunctional or no protein

In humans, do many traits involve multiple genes and show simple Mendelian patterns

no

_ single-gene traits, often for disease —

• ~ 7000, phenotypes

the most common single gene traits in humans (know recessive vs dominant)

recessive

• thalassemia (less hemoglobin)

• sickle cell disease

• cystic fibrosis

• tay-sachs disease (missing enzyme, disrupts brain development)

• phenylketonuria (missing enzyme, intellectual disability)

dominant

• hypercholestrolemia (removes cholestrol from blood)

• huntington disease (nervous system damage)

Pedigrees Aid the Study of __ Traits in Humans

Hereditary

• Humans __ amenable to traditional genetic crosses

– not

Pedigree

orderly diagram of family's relevant genetic features • Include as many generations as possible

• Both sets of grandparents of affected person

Vertical pattern

affected people have at least one affected paren

• If trait is rare, vertical pattern suggests disease allele is __

dominant

Recessive, rare genes

few affected people would have affected parents • Common recessive traits can show a vertical pattern

Affected individuals with no unaffected offspring most likely __ as disease allele is _

heterozygotes , rare

Fig. 1.19 Why the allele for Huntington disease is dominant.

People who are HD HD or HD HD+ exhibit Huntington disease because the HD allele produces an abnormal Htt protein that damages nerve cells. Homozygotes for the normal allele (HD+ HD+) produce only normal Htt protein and do not have the disease. The disease allele (HD) is dominant because even when the normal protein is present—in HD HD+ heterozygotes—the abnormal protein damages nerve cells. HD HD homozygosity is possible because the abnormal Htt protein retains some function of the normal protein.

Horizontal pattern

: parents, grandparents, etc. of affected individual are typically not affected but siblings may be

• If trait is rare, parents of affected individuals are heterozygous carriers of recessive allele (vs affected)

Consanguineous mating increases risk, as related individuals are more likely to both be carriers

Consanguineous mating

incestt

Why the cystic fibrosis disease allele is recessive.

The CFTR protein regulates the passage of chloride ions (green spheres) through the cell membrane. Homozygotes for a cystic fibrosis disease allele (CF CF) have the disease because recessive disease alleles either specify no CFTR protein as shown, or encode abnormal CFTR proteins that do not function at all or function less well than the normal protein (not shown). Disease alleles (CF) are recessive because CF CF+ heterozygotes produce sufficient CFTR from the normal (CF+) allele for normal lung function.

How to recognize dominant traits in pedigrees

1. affected children always have at least one affected parent

2. dominant traits show a vertical pattern of inheritance. the trait shows up in every generation

3. two affected parents can produce unaffected children, if both parents are heterozygotes

how to recognize recessive traits in pedigrees

1. affected individuals can be the children of two unaffected carriers, particularly as a result of consanguineous matings

2. all the children of two affected parents should be affected

3. rare recessive traits show a horizontal pattern of inheritance. the trait first appears in one or more members of one generation and is not seen in earlier generations

4. recessive traits may show a vertical pattern of inheritance if the trait is extremely common in the population

Dominance Is __ Complete

Not Always

Incomplete dominance

The F1 hybrid resembles neither true-breeding parent

• 1:2:1 genotypic ratio indicates a single gene trait

• Phenotype ratio is 1:2:1 instead of 3:1

• Hybrid genotype now has own phenotype

Codominance

The F1 hybrids exhibits traits of both parents

• Phenotype ratio = genotype ratio = 1:2:1

human blood groups

Example of codominance

• Gene I controls type of sugar polymer on surface of red blood cells

• Alleles IA and IB produce different sugars

• IA IA individuals have A sugar

• IB IB individuals have B sugar

• IA IB individuals have both A and B sugars

• Different alleles each produces a functional product, codominant at molecular level

Different dominance relationships.

• Phenotype ratio matches genotype ratio, heterozygotes have new phenotype

• Dominance relationship depends on proteins encoded and biochemical function

Does Mendel’s law of segregation still hold for codominance

yes

Can genes have more than two alleles

yes

• Dominance relationships are considered in

pairs

Dominance series

most dominant to most recessive allele

• Alleles not inherently dominant or recessive

• Relationship unique to each pair

• 3:1 or 1:2:1 ratio in F2 of each cross confirms alleles of one gene

ABO blood types for dominance series

• 3 alleles in human population

• IA allele - A type sugar

• IB allele - B type sugar

• i allele - no sugar

• 6 genotypes possible

• 4 phenotypes or blood groups

• A, B, AB, O

• Dominance relationship: IA = IB > i

• IA and IB codominant

• IA and IB each dominant to i

• Legal and medical implications

__Are the Source of New Alleles

Mutations

mutation

• Mutation occurs spontaneously in nature

• ~ 1 gamete in 106 carries a new mutation in a given gene

• Mutation makes it possible to follow gene transmission

allele frequency

proportion of a particular in a population

• Population of 50 individuals, what is the frequency of an allele found in 10 homozygotes and 5 heterozygotes? – 25%

wild-type allele

a common allele in the natural population

mutant allele

rare or newly-arisen allele (or in lab population)

monomorphic

a gene with only one common wild-type allele

agouti gene in mice

• The agouti gene in mice is monomorphic with one wild-type allele in the wild, but many mutant alleles in laboratory mice

Polymorphic gene

>1 common allele in population

High-frequency alleles of a polymorphic gene - common variants vs wild-type

ABO blood type gene is polymorphic – all 3 alleles are common variants

Pleiotropy

a single gene determines several distinct, seemingly unrelated characteristics

• Many genes have pleiotropic effects

• Most proteins act in different tissues or biochemical pathways

• Example: Respiratory problems and sterility in Maori males of New Zealand

Recessive lethal allele

affects both a visible phenotype and viability

• Example: AY allele of agouti gene in mice

• AY allele causes yellow hairs with no black

• AYAY do not survive

• Cross inbred agouti mice with yellow mice

• F1 is 1:1 ratio of agouti to yellow

• Yellow mice heterozygous – AYA

• AY dominant to A for hair colour

• Cross yellow x yellow mice

• F1 2/3 yellow, 1/3 agouti

• Yellow mice heterozygotes

• AYAY mice not viable

• AY recessive to A for lethality

• Pleiotropic effects often include lethality in an organism’s life cycle

• eg. Tay-Sachs disease in humans

• Dominant/recessive not absolute even for specific pair of alleles

• 2:1 ratio → recessive lethality

what are the phenotypic ratios of all the alterations of mendels 3:1 ratio

incomplete dominance - 1:2:1

codominance - 1:2:1

multiple alleles - 3:1 or 1:2:1

pleiotropy - depends on dominance relations

recessive lethal alleles - 2:1 (1/4 dies)

ratio of f2 for complete dominance in 2 alleles of 2 genes that assort independently

9:3:3:1

Additive Interactions Between Two Genes Controlling a Single Trait

• Dihybrid cross of lentils, tan x grey

• All F1 seeds brown

• F2 progeny: • 9/16 brown; 3/16 tan; 3/16 grey; 1/16 green

• 9:3:3:1 ratio in F2 - two independently assorting genes

• Two genes interact additively to produce trait phenotype

• Novel phenotypes not seen in parents

• 4 phenotypes of one trait

• Dominant allele of both genes = brown

• Dominant of one gene = tan

• Dominant of other gene = gray

• No dominant = green Two independent biochemical pathways

Epistasis

• An allele at one gene masks the phenotypic effect of another gene

• gene that masks is epistatic

• gene that gets masked is hypostatic

• 4 genotype classes produce <4 phenotypes

Recessive epistasis

• Hypostatic gene masked by homozygous recessive epistatic gene

• Example: Labrador retriever dogs

• ee masks phenotype of gene B

• 9:3:4 ratio in F2 progeny of dihybrid cross

• 9/16 black (B- E-)

• 3/16 brown (bb E-)

• 4/16 yellow (-- ee)

• Protein E is necessary for expression of any genotype of gene B

• B and E genes function in same pathway

Bombay phenotype

• H gene governs production of polymer that attaches A/B sugars to blood cell surface

• hh produce no substance H, O phenotype regardless of genotype of I gene

• h, the Bombay allele, is epistatic to I gene

Dominant epistasis

• Hypostatic gene masked by dominant allele of epistatic gene Example: Squash fruit colour

• At A gene: A- are yellow; aa are green

• At B gene: B- are white, bb are yellow or green depending on A genotype

• Dominant B allele of gene B masks effects of gene A

• 12:3:1 ratio in F2 progeny of dihybrid cross

• 12/16 white (A—B—, aaB-)

• 3/16 yellow (A—bb)

• 1/16 green (aabb)

• Protein B prevents the deposition of either green or yellow pigment

• Genes A and B have antagonistic functions

phenotypic ratios of two-gene interactions

additive - 9:3:3:1

recessive epistasis - 9:3:4

reciprocal recessive epistasis - 9:7

dominant epistasis 1 - 12:3:1

dominant epistasis 2 - 13:3

redundancy - 15:1

Locus Heterogeneity

Mutations in Any One of Several Genes May Cause the Same Phenotype

property of a trait where mutations in any one of two or more genes results in the same mutant phenotype

• Examples: loss of hearing in humans

• ~ 50 genes have recessive mutant alleles that cause deafness in humans

• A dominant allele is required at all genes for typical hearing

Heterogeneous trait

a recessive phenotype caused by mutations in different genes

Evidence for locus heterogeneity in human pedigrees

• If two people with loss of hearing have hearing children, they are homozygous recessive at different genes - complementation

• If they have only children who also have hearing loss, then they are likely homozygous recessive for the same gene

• Complex traits

• traits controlled by the interactions of multiple genes

• polygenic

• Or interaction of many genes and environmental factors

• multifactorial

Penetrance

percentage of population with a particular genotype that show the phenotype

• Complete – all yy peas are green, all Yy or YY peas are yellow

• Incomplete – retinoblastoma – not all Rb+Rb individuals develop tumours

Expressivity

- intensity which a particular genotype is expressed in phenotype

• Unvarying – all yy peas the same shade of green?

• Variable – retinoblastoma – single or multiple tumours in 1 or 2 eyes

• Modifier genes • environmental effects • chance