Genetics Test 3

Null hypothesis

• assumes data will fit into given ratio

  • no difference between observed and expected

  • any difference is by chance

• Can never be proven, only supported

  • fail to reject = support

Chi square

• goodness of fit

• influence of chance on data

• whether data is consistent with model

• Too different to not be by chance? = null rejected

• Due to random fluctuations = fail to reject null

P-value

• significant differences between datasets

• frequently 0.05 → 5% you would observe same variation or greater

  • greater than 0.05 = fail to reject

  • less than 0.05 = reject null

Chi square equation

= sum of (o-e)²/e

Linkage

genes (alleles) on the same chromosome are likely to be inhereited together

• linked genes

• two genes on a single pair of homologs; exchange occurs between two nonsister chromatids

Linkage group

set of linked genes

• on chromo 4 = linkage group

Genetic map

shows the order of linked genes and distances between genes on a chromosome

• constructed based on recombination frequency between genes of interests observed during test crosses

The further apart two genes are

the more likely recombination will occur

• happens every meiosis cycle

• lots of space for crossing over

OR

• two genes have less space between them and are unlikely to be separeted by crossing over

Frequency of recombination measured by

• Determine the distance between genetic markers or physical markers and construct a map

• test cross with F1 heterozygotes with homo recessive

• two genes? two point cross

• classify F2 as recombinant or parental

Physical marker

phenotype associated with a gene locus

Genetic marker

DNA sequence, such as SNP or repeat

Recombinant progeny

progeny that is different than parental

• parental is vice versa

Distance of genes on a map formula

(number of recombinants / total progeny) (100)

Double crossover (DCO)

Double crossover occurs when two chiasmata form and there is a double exchange between two nonsister chromatids

The expected frequency of DCO gametes is much lower than

that of either single crossover gamete class

• 
  

Three point test cross likelihoods

• progeny in the lowest abundance are DCO recombinants

• Progeny in the highest abunadance are parental

• progeny intermediate in their abundance are single crossover recombinants

Distance between genes steps

1. order of genes

2. reorganize to gene order

3. MU for first two genes

4. MU for second two units

Genotypic sex determination

due to specific DNA sequences

Genic balance

ratio of sex chromosomes to autosomes controls the amount of sex determining gene products

Chromosome determination

whether specific gene product(s) encoded in a sex chromosome are present or absent; presence or absence of a sex chromosome

Mating-type determination

expression of gene variants called idiomorphs control mating type (in some haploid microbes)

Environmental sex determination

signals from environment

• ex: day length, temperature, social cues

Y chromosome determination in humans

• XX causes gonads to develop into ovaries and produce eggs

  • WT biological female

• XY causes gonads to develop into testes and produce sperm

  • WT biological male

Y chromosome pieces

• PAR = Psuedoautosomal region

• SRY = Sex determining region Y

• MSY = Male specific region of the Y

Genes present on X and Y chromosomes

• many linked genes do not influence sex development

• Most sex linked genes are X linked because Y doesn’t contain many genes

X linked recessive inheritance

More frequently observed in males

• Males are hemizygous for genes on X chromosome

  • No second allele to compensate for recessive allele

• Females express the trait when they are homozygous for the allele

  • Female heterozygotes are carriers

Barr bodies are inactive X chromosomes

• During blastocyst stage, an X is deactivated in XX mammals

• Barr body is made of heterochromatin

• A form of imprinting

  • monoalleleic expression → gene dosage compensation

  • equal amounts of X linked expression betwen males and females

Number of Barr bodies in somatic cells

all X chromosomes except one are deactivated

Barr body formed through lyonization 

1. Involves XIST gene on X chromosome

• Weakly expressed from both X chromosomes

2. During early development, one XIST gene copy is silenced

• This X chromosome becomes the active X chromosome

• Other X chromosome continues to express XIST and becomes the Barr body

3. XIST encodes a long non-coding RNA (lncRNA)

• Coats chromosome and recruits epigenetic machinery (DNA methyltransferases and HDAC) to pack up the chromosome

4. 
   

Mosaicism

Multiple alleles

• Most genes have >2 alleles in a population

  • A single diploid can have up to 2 alleles for a given gene

• New alleles arise through mutation

• hierarchy of dominance ex: the three eye colors of flies,

  • red-most

  • eosin-mid

  • white-least

Calculating the number of possible genotypes in a population

• n = number of alleles

• possible genotypes are (n)(n+1) / 2

Codominance

• Heterozygotes simultaneously show the phenotypes that would be seen in the homozygotes

  • In a heterozygote, the two phenotypes resulting from both alleles can be observed

  • no blend

Molecular explanation of codominance

• Equal amounts of gene product from both alleles

• Both alleles are expressed and have equal activities

• Gene products don’t interfere with each other

Incomplete dominance

• One allele is not completely dominant to the other

• blend is present

Molecular explanation of incomplete dominance

• Varies from trait to trait

• Can be dependent on gene dosage

  • Homozygosity for functional allele causes two doses of the gene product 

  • Heterozygosity causes one dose

  • Homozygosity for the null allele no dose

Pleiotropy

• single gene, multiple phenotypes

• PKU

• Molecular explanations

  • Promiscuous protein has more than one function 

  • Cell-specific effects of protein variants

Essential gene

gene product required for life of cell/organism

• No compensating gene or gene with redundant function to take its place

• When mutated in a way that changes the function of the gene product, a lethal allele results

Lethal allele

presence results in death of organism

• A.k.a. deleterious allele

• Different than a null allele, although a lethal allele can also be a null allele

Polygenic traits

• Multiple genes contribute to a trait

• Most traits result from the combinatorial action of multiple alleles of multiple genes 

  • Example: lots of genes encode growth factors and growth factor receptors to influence human height

  • Example: autism

  • Coat color in mice

  • Eye color

Epistasis

• two genes involved

• form of gene interaction in which one gene interferes with the expression of another gene

• epistatic gene supresses the phenotype from the hypostatic gee

Extranuclear Inheritance

Transmission of information to offspring occurs through something in the cytoplasm 

• phenotype not caused by own nuclear genome

• non-medelian

• Varieties in extranuclear inheritance

  • Organelle heredity - mt and cp

  • maternal effect - RNA and proteins in cytoplasm of egg

  • infectious heredity - DNA from microbes and viruses

Organelle heredity

• Ancient eukaryotic cell engulfed prokaryotic cell (endosymbiotic theory)

  • Ability to make more energy was selected

  • Engulfed cell eventually became the mitochondria or chloroplast 

• Mitochondria split by fission

  • Cells have lots of mitochondria (not just one)

  • Progeny cells inherit mitochondria and therefore mtDNA from the parent cell during cell division

• Number of mitochondria vary from cell to cell 

  • Cells with high energy demands (muscle, neurons) have more mitochondria per cell

Organelle heredity in mammals, yeast, and plants

• mtDNA inherited from female parent via the egg

  • sperm mitochondrai is degraded

• Fungus

  • inhereited from both parents bc both cells fuse

• Plants

  • cp varies

Heteroplasmy

mitochondria or chloroplasts from different sources and/or of varying genotypes

• mixture of mito/cp from both parents

• mixture of mito/cp genotypes within a cel or within a multicellular organism due to mutation

Molecular organization of mitochondria (mtDNA)

• DNA in mito is unlike DNA in nucleus of euk cells that house these organelles

• circular

• no histone or introns

• few gene products encoded

  • most RNAs and proteins found in mito are encoded in nucleus

mtDNA mutations

• Damage due to

  • ROS

  • No protection from histones

  • DNA repair is limited

    • in nuclear genome

• Used to trace ancestry (maternal haplogroup)

• Mutations can cause human disease

Maternal effect

• offspring phenotype is under control of nuclear gene products present in egg

• nuclear genes of female gamete transcribed; gene products accumulate in egg cytoplasm

• products are given to newly formed cells, influencing patterns and traits establshd in ealy development

Polarization

which side of embryo will be posterior or anterior

Testcross

cross genotype with homozygous recessive (tester)

3 point testcross steps

1. order of genes

2. distance between first two

3. distance between other two

Limits to genetic maps

• DCO do not happen as often as predicted because of interference 

  • One chiasma inhibits formation of another chiasma

• Crossing over doesn’t occur at random.  

  • Chromosomes have recombination hot and cold spots 

• Sometimes a DCO event can look like the parental phenotype, skewing the data 

  • The farther apart two genes are, the greater the probability that undetected double crossovers will occur

• Unrealistic to use the same methods as model organisms 

  • ethics, takes a long time, low sample size

• Can do: Analyze DNA markers (SNPs, microsatellites) using positional cloning, DNA arrays, and genome sequencing 

Aneuploid conditions

• 45, XO (Turner syndrome) are female

• 47, XXY (Klinefelter syndrome) are male

Sex reversal conditions

• 46, XY females with deletion of the Y chromosome

• 46, XX males had a small piece of Y attached to X

• Same chromosome region involved in both cases

Hypothesis: The chromosome region translocated in both XY females and XX males is

essential for an individual to develop testes

SRY discovered using transgenic mice

• Experiment: Equivalent region from mouse was introduced into XX mouse embryos.

  • Controls: Untreated XY and XX littermates

• Result: Male sexual development in XX mice.

• Conclusion: SRY is required for male testes development.

The effect of SRY in mammalian sex

• SRY is expressed about 6-8 weeks after fertilization

• Activates SOX9 gene expression

  • controls the expression of genes involved in testes development 

  • Represses WNT4 gene expression

    • signaling protein that activates ovary development via B-catenin pathway

Which statement best describes wild-type human sex determination?

1. Females are heterogametic.

2. Individuals with a Y chromosome are male.

3. Individuals with two X chromosomes are female.

4. Individuals with at least twice as many X chromosomes as Y chromosomes are female.

5. Individuals with one X chromosome are male.

Individuals with a Y chromosome are male.

A karyotype is done on an individual who has ovaries and no testes, and it is discovered that they are XY. However, the Y chromosome appears to have a deletion. What region is most likely deleted?

1. PAR

2. SRY

3. centromere

4. MSY

5. heterochromatin of MSY

SRY

X linked recessive inheritance proportions

1. What proportion of the sons of an affected XX mother would show the trait?

2. What proportion of the sons of a carrier XX mother would show the trait?

3. What proportion of XX daughters would show the trait from an affected XX mother and unaffected XY father?

1. 100%

2. 50%

3. 0%

A young XY boy is diagnosed with hemophilia A, a recessive, X-linked condition. If neither parent has hemophilia A, what are their probable genotypes?

1. X^AX^a, X^AY

2. X^AX^A, X^aY

3. X^aX^a, X^AY^A

4. Mother could be either X^AX^A or X^AX^a, but father is X^aY

5. cannot predict from the information given

X^AX^a, X^AY

X-linked dominant inheritance

1. If the XX mother is heterozygous and XY father is unaffected, what proportion of their XY sons will be affected? XX daughters?

2. If the XX mother is unaffected but the XY father is affected, what proportion of their XX daughters will be affected? XY sons?

1. 50% and 50%

2. All daughters, no sons

What does mosaic mean in genetics? How is it related to XX mammals?

Cells within mutlicellular organisms have different genotypes

• 2 ways

  • new mutation during development in a cell

  • Bar bodies in XX females

Colorblindness is an X-linked, recessive trait. The XY father of a family is colorblind while the XX mother has wild-type color vision and has no family history of colorblindness. Their XX daughter displays mild color perception deficits. What might explain her phenotype?

1. She is homozygous for the mutant allele

2. She is a mosaic

3. She is intersexed

4. She has a de novo mutation in the photoreceptors

5. She is hemizygous for the mutant allele

She is a mosaic

Which of the following describes Lyonization as a process? 

1. Barr bodies are inactivated X chromosomes.

2. The paternal X chromosome of a female is inactivated in an early embryonic stage.

3. The maternal X chromosome of a female is inactivated in an early embryonic stage.

4. One of the two female X chromosomes is randomly inactivated in an early embryonic stage.

5. As a child grows, each cell of a female randomly inactivates one X chromosome shortly after mitosis.

One of the two female X chromosomes is randomly inactivated in an early embryonic stage.

A male observed his stained epithelial cells and saw a Barr body. If a karyotype was performed on his cells, what would you expect to see? Choose all that apply.

1. 46, XY

2. 46, XX

3. 47, XXY

4. 47, XYY

47, XXY

Drosophila melanogaster, like humans, have X and Y chromosomes so that XX is female and XY is male. However, unlike humans, it is the ratio of the number of X chromosomes to sets of autosomes that determines the sex of the fly. A fly has one X chromosome, two sets of autosomes (a diploid set), and no Y. What is its predicted sex?

1. male

2. female

3. intersex

male

You observe the cells and karyotypes of a novel species of mammal found on an island. No females have a Barr body; however, they all have two X chromosomes. Males have one X and one Y chromosome. Considering dosage compensation, which of the following would you predict?

1. Males transcribe their X at twice the rate of a female X.

2. Males transcribe their X at half the rate of a female X.

3. Females transcribe their X at twice the rate of a male X.

4. Transcription rates would not be affected.

Males transcribe their X at twice the rate of a female X.

Xist lncRNA plays a crucial role in X inactivation. The Xist RNA coats the X chromosome that produced it, and whichever X has more Xist, it becomes the inactive X. If a mutation inactivated Xist on only one chromosome, what would you predict to occur?

1. The mutant chromosome would always be inactivated.

2. The mutant chromosome would always be active.

3. Both chromosomes would be inactivated.

4. Both chromosomes would be active.

5. The wild-type Xist would compensate for the mutant, and X inactivation would proceed normally.

The mutant chromosome would always be active.

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