Ch 5 Complex Phenotypes and Gene Interactions

pseudoautosomal inheritance

• refers to the very few genes found on both X and Y chromosomes

• these genes behave like autosomes (non-sex chromosomes)

• other genes on the X are not present on the Y, making males hemizygous (only one copy of an allele instead of 2)

hemizygous

• only one copy of an allele instead of 2

• ex., Y chromosome has few genes

Y chromosome

• ? chromosome is shrinking

• full of repetitive sequences

• very difficult to sequence the Y chromosome

• complete sequence published in 2023 (for regerence, the 1st RD of human reference genome was published in 2000…)

• little sequence variation in Y chromosome between father and son with no recombination to maternal chromosomes

  • recombination: pieces of DNA exchanged between homologous chromosomes->new combinations of alleles and creating genetic diversity in offspring (different than crossing over)

    • can trace Y chromosome directly to father, paternal grandfather, etc.

little recombination on y

• little sequence variation in Y chromosome between father and son with no recombination to maternal chromosomes

  • recombination: pieces of DNA exchanged between homologous chromosomes->new combinations of alleles and creating genetic diversity in offspring (different than crossing over)

  • can trace Y chromosome directly to father, paternal grandfather, etc.

• 8% of men in 16 populations spanning Asia (and 0.5% of men worldwide) share nearly identical Y chromosome sequences. The variation that did exist in their DNA suggested that the lineage began around 1000 years ago in Mongolia (prob relatives of Genghis Khan)

sex linked genes

• found on 1 of the 2 types of sex chromosomes, but not both

X linked

• hemizygous in males

• only 1 copy

• males are more likely to be affected (as they only inherit 1 copy of X chromosome)

Y linked

• relatively few genes in humans

• referred to as holandric genes

• transmitted only from father to son (female has no Y chromosome)

punnet squares of X-linked traits

• punnett square show different results depending on which sex is affected

• Male can transmit his one X or Y chromosome

• Affected males can’t have an affected male offspring unless the female is a carrier (bc the X chromosome for sons will only ever come from mom)

• patterns observed vary greatly from expected Mendelian ratios depending on whether males or females harbor the alleles

pedigree for X linked disease

• pedigree for ? shows that it is mostly males that are affected with their mothers as carriers

• all female carriers crossed to unaffected males

  • unaffected males can’t have affected female offspring

    • they always give dominant, wild type allele to daughters

      • logic (daughter gets 1 X from dad, and if he’s unaffected with a dominant, wild type allele…)

lethal alleles

• have the potential to cause the death of an organism

• result of mutations in essential genes (required for survival)

• often recessive

• only around 1/3 of all genes are thought to be essential for survival

• may produce ratios that seemingly deviate from Mendelian ratios (due to the absence of homozygous carriers)

  • these individuals are not counted, bc THEY DON’T SURVIVE LONG ENOUGH TO BE COUNTED

• ex., manx cat

  • dominant mutation that affects the spine and shortens the tail

  • this allele is lethal as a homozygote

  • 1:2 ratio of kittens that are born

    • Rather than expected 3:1 (since AA is not present to be phenotyped)

pleiotropy

• single gene causes multiple phenotypes

• can be caused bc

  • the gene product can affect cell function in more than one way

  • the gene may be expressed in different cell types

  • the gene may be expressed at different stages of development

• major consideration in disease, developmental, and evolutionary biology

• ex., cystic fibrosis

  • functional (wild-type) allele encodes the cystic fibrosis transmembrane conductance regulator (CFTR_

  • regulates ionic balance by transporting Cl- ions

  • mutant doesn’t transport Chloride effectively

    • in lungs, this causes very thick mucus

    • on the skin, causes salty sweat

    • poor weight gain due to blockages in tubes that carry digestive enzymes

• ex., biased patterns of gene loss in icefishes

  • ? score = number of non-blood associated phenotypes in mouse mutants

more than 1

• most genes affect ? traits

pleiotropy

• ex., cystic fibrosis

  • functional (wild-type) allele encodes the cystic fibrosis transmembrane conductance regulator (CFTR_

  • regulates ionic balance by transporting Cl- ions

  • mutant doesn’t transport Chloride effectively

    • in lungs, this causes very thick mucus

    • on the skin, causes salty sweat

    • poor weight gain due to blockages in tubes that carry digestive enzymes

• ex., biased patterns of gene loss in icefishes

  • ? score = number of non-blood associated phenotypes in mouse mutants

lethal allele

• ex., manx cat

  • dominant mutation that affects the spine and shortens the tail

  • this allele is lethal as a homozygote

  • 1:2 ratio of kittens that are born

    • Rather than expected 3:1 (since AA is not present to be phenotyped)

gene interactions

• gene products (usually proteins) function in a soup of thousands of other gene products inside of living cells

  • the impact of gene mutations therefore usually depends on the broader context of what else is happening inside the cell

• gene interactions occur when 2 or more different genes influence the outcome of a single trait

• nearly all traits are affected to some extent by contributions of many genes

• morphological traits like height, weight, and pigmentation are affected by many different genes in combination with environmental factors

• ex., complementation: 2 affected parents with unaffected offspring due to having mutations in separate genes (which functionally complement each other)

• ex., epistasis: one gene masks phenotype of an allele of another gene

• ex., modifier: one gene “modifiers" phenotype of an allele of another gene

• ex., redundancy: mutation in >=2 genes necessary for phenotype

complementation

• two affected parents have unaffected offspring due to having mutations in separate genes (which functionally complement each other)

• 2 genes can both, independently, cause purple flowers

• cross of 2 true-breeding recessive traits results in a dominant phenotype

  • very suggestive of ?

  • suggests white mutations are on different genes in each parent

  • the 2 genes have complementary roles, can both lead to a phenotype

epistasis

• one gene masks phenotype of an allele of another gene

modifier

• one gene “modifier” phenotype of an allele of another gene

redundancy

• mutation in >=2 genes necessary for phenotype

complementation test

• if you have 2 strains of white flowered plants- are they caused by alleles of the same gene or alleles of different genes?

• if there is complementation (e.g., 2 recessive traits crossed show the wild-type phenotype), this indicates phenotype caused by multiple genes

• if there is no complementation, (trait remains true-breeding), phenotype caused by alleles of 1 gene

• ? refers to cases where alleles of two different genes cause the same phenotype

• if the mutation is in the same gene- they won’t complement

• If phenotypes are caused by different genes, each strain is likely wild-type at the other strain’s gene

• this makes things behave as a 2 gene cross, leading to the appearance of the wild-type trait in the F1

epistasis

• a gene masks the phenotypic effects of another gene

• epistatic interactions often arise because 2 (or more) different proteins participate in a common cellular function

• homozygous alleleic version of either white gene (cc or pp) both of which lead to white flowers

  • Both C and P genes required for purple flowers

  • form of ? (e.g., dominant C or P allele) masks purple (wildtype) phenotype of other gene)

    • ex., though Pp or PP should be purple, it’s phenotype is white because of cc

    • in this cross, purple/white flowers appear in 9:7 ratios in F2 generation

modifiers

• unlike epistasis (which masks), ? ALTER the phenotype

• alleles of one gene modify the phenotypic affect of another

• ex., coat color in mice

  • black- all eumelanin

  • brown/agouti- bands of eumelanin/phaeomelanin

  • albino- no melanin

    • F1: true breeding black mouse x true breeding albino results in agouti color

    • F2: 9 agouti: 3: black 4: albino (when have confusing phenotypic ratios, use punnett squares)

      • assume a 2 locus (dihybrid) cross, and that we know parents were true breeding (homozygous)

        • each F1 is AaCc

          • true breeding P are: aaCC(black) or AAcc (albino)

          • trick is to find a coherent combo of genotypes that match the phenotypes

        • result:

          • Aa/AA- brown (mix of black and yellow)

          • aa: black throughout entire hair

          • cc no pigmentation

        • one copy of each dominant allele results in agouti color

        • one dominant C but recessive aa will be black

        • the four cc animals are albino, even if the dominant A is present

          • c is epistatic to A

          • (aa can also be considered epistatic to C where aa modifies agouti to black)

• caused by 2 genes

gene redundancy

• one gene compensates for the function of another

• common with loss of function alleles (mutations that eliminate the activity of gene products)

  • here, another gene product accomplishes the task missing from the loss of function mutation

• can create loss of function in the lab- gene knockout

  • random mutagenesis, CRISPR/Cas9 genome editing

• gene duplication results in the creation of one or more copies of a gene that become more divergent over time

  • duplicated genes are paralogs

  • one gene copy can compensate for loss of function in another

• other proteins carry out similar functions, enough to compensate for losses

• (altered) phenotype only when both redundant genes are lost

• ex., seed capsule shape

  • P: triangular x ovate

  • F1: all triangular

  • F2: 15 triangular:1 ovate

    • only recessive for both genes (ttvv) is ovate

    • T and V have redundant function (takes loss of both to see phenotype)

paralogs

• duplicated genes

pleiotropy

• gene does >1 thing

epistasis

• gene masks mutant allele of another gene

complementation

• phenotype due to mutations in separate genes

modifier

• gene changes the phenotype of another gene’s allele

redundancy

• need mutations in greater than or equal to 2 genes for a trait

complementation test

• if you have 2 strains of white flowered plants- are they caused by alleles of the same gene or alleles of different genes?

• if there is ? (e.g., 2 recessive traits crossed show the wild-type phenotype), this indicates phenotype caused by multiple genes

• if there is no ?, (trait remains true-breeding), phenotype caused by alleles of 1 gene

complementation test

• If phenotypes are caused by different genes, each strain is likely wild-type at the other strain’s gene

• this makes things behave as a 2 gene cross, leading to the appearance of the wild-type trait in the F1

• so for this cross:

  • wildtype B allele from strain 1 rescues the recessive b allele from strain 2

  • wildtype A allele from strain 2 rescues the dominant a from strain 1

complementation table

• failure to complement (-) means the strains have mutations in the same gene

• complementation (+) means we have different genes

• strains will always fail to complement themselves (-)

• the best way to solve these is to go one row or column at a time, and gradually build up complementation groups each time you encounter failure of complementation (-)

• In this table, we find that 1=3=6, 2=4, 5=7. So we have isolated variants in 3 different genes from our screen as causing the albino trait

• In other words: 1,3 and 6 are alleles of the same gene, 2 and 4 are likely alleles of the same gene, but 2/4 is a different gene than 1/3/6

complementation

• same phenotype caused by mutations in different genes

3

Here are the results of a complementation test. How many genes are mutated across these 7 strains?

redundancy

A 15:1 F2 phenotypic ratio of a dihybrid cross is typical of

complementation

A phenomenon where two affected, recessive parents have unaffected offspring?

Allele is lethal in homozygotes

You expect a 3:1 ratio of phenotypes from a F2 monohybrid cross. Instead you observe 2:1. What might be happening?

pleiotropy

A mutation in a single gene impacts flower color and plant height. This is an example of:

modifiers

You cross two brown mice together and get a 9:3:4 phenotypic ratio of brown:black:white mice. What is happening?

epistasis

Deep in the heart of a top secret McDonald's research facility, you breed two purple Grimaces together and a get 9:7 ratio of purple to white Grimaces. What could explain this outcome?

1, hemizygous

Human males have ___ copies of the X chromosome, making genes on this chromosome ___