BS1050- transmission genetics l5/6

Lecture 5- transmission genetics

What is dominance

When 2 alleles of the same gene interact and one masks the efect o the other

complimentation test

Mutations are in different genes and each gene provides what the other lacks- both genes are expressed (uses 2 genes each with 2 alleles)

(Complementation occurs when two genomes with mutations in different genes restore normal function when combined, as each provides a functional copy of the gene the other lacks.)

Recombination frequency

Counts of offspring phenotypes used to calculate RF

RF= Recombinant offspring/total offspring x 100

What a a recombinant and parental

Offspring with new allele combinations produced by crossing over during meiosis

So parental: offspring with the same combination of alleles as the parents (no new combinations)

Recombinant types are offspring with new combinations of alleles

• Formed due to crossing over during meiosis (prophase I)

• Usually less frequent (if genes are linked)

Linkage

-alleles of different loci on the same chromosome, consecrate at meiosis, do not assort independantly

RF of loci

Genes on the same chromosome tend to be inherited together → linkage

RF of less than 50% indicates linkage

Why 50%

Why 50% is the cutoff

• Genes on different chromosomes (or very far apart on the same one) assort independently

• Independent assortment produces:

• 50% parental types

• 50% recombinant types

➡️ RF = 50%

So:

• RF < 50% → genes travel together more often → linked

• RF = 50% → genes behave as unlinked

What does RF show

RF tells you how strongly two loci are linked.

• Low RF (e.g. 5%) → genes are very close together

• Higher RF (e.g. 30%) → genes are further apart

• RF approaches 50% → weak or no linkage

Crossing over is more likely between genes that are far apart

• Genes close together are rarely separated

Loci can be ordered on a genetic map based on RF

By comparing RF values between multiple gene pairs, you can work out:

• Which genes are closest

• Which are further apart

• The order of genes on the chromosome

• Smallest RF → closest genes

• Largest RF → genes furthest apart

• Middle RFs help place genes in between

One centiMorgan represents a 1% probability of recombination between two loci.

Sex linked inheritance X

X-linked inheritance

• Genes on X chromosome

• Males (XY) express recessive alleles immediately

• Females (XX) can be carriers

Classic pattern

• More males affected

• No father-to-son transmission

Sex linked inheritance Y

• Genes on Y chromosome

• Passed father → son only

• Rare, but very distinctive inheritance pattern

Mitochondrial DNA

• Mitochondrial DNA inherited from mother only (only the egg contributes mitochondria to the embryo)

Key rules

• Mothers pass it to all children

• Fathers pass it to n

Lecture 6- medical genetics

Hemizygous

means having only one copy of a gene instead of the usual two.

What type of things to mention when analysing a pedigree

-Hemizygous males and

heterozygous females equally

affected

• Heterozygous 'affected'

females have 50% chance of

having affected offspring

• Affected males cannot give

trait to sons, but will give it to

all their daughters

Chromosomal abnormalities - numerical

Polyploidy

Multiple of haploid number (e.g. triploidy 3n=69

Aneuploidy

Abnormal number of chromosomes (e.g. monosomy 2n-1=45

or trisomy 2n+1=47)

structural

• Unbalanced

e.g. deletion, insertion/duplication, ring chromosome

• Balanced (in many but not all cases)

e.g. inversions (An inversion is when a section of a chromosome breaks off, flips, and reattaches in reverse order) translocations (segment of one chromosome moves to another chromosome)

How does aneuploidy occur

The presence of extra of missing individual chromosomes due to errors in chromosome segregation

Usually caused by nondisjunction during meiosis:

• Homologous chromosomes (meiosis I) or

• Sister chromatids (meiosis II) fail to separate

Trisomy (2n + 1) → one extra chromosome

Example: Down syndrome (trisomy 21)

• Monosomy (2n − 1) → one missing chromosome

Example: Turner syndrome (45,X)

(Non disjunction means chromosomes fail to separate properly during cell division)

Difference between aneuploidy and polyploidy

How it's different from polyploidy

• Aneuploidy → gain/loss of individual chromosomes

• Polyploidy → gain of entire chromosome sets (e.g. 3n, 4n)

Rate of non-disjunction

aneuploidy = 10-30% of human fertilized eggs

• ~95% of gametic aneuploidy originates during

oogenesis (the process by which female gametes are produced in the ovaries)

• frequency of errors increases with female age

-vulnerability of chiasmata, cohesion's and segregation machinerary increase with age

Non-disjunction diagram in mitosis

Conditions from trisomy

trisomy 13 - Patau syndrome

trisomy 18 - Edwards syndrome

trisomy 21 - Down syndrome

Sex determination in mammals

SRY (Sex-determining region Y) is a sex-determining gene on the Y chromosome of mammals

This intronless gene encodes a transcription factor that is the testis determining factor (TDF). The SRY (or TDF) protein initiates male sex determination. Mutations in this gene give rise to XY females with gonadal dysgenesis (Swyer syndrome). Translocation of part of the Y chromosome containing this gene

to the X chromosome causes XX male syndrome

SRY purpose

SRY (Sex-determining Region Y) is:

• A gene located on the Y chromosome

• Intronless (no introns)

• Encodes a transcription factor called TDF

Whaat is SRY

SRY is the master switch for male development

• When expressed in the embryo:

• It activates genes that cause testis formation

• The testes then produce:

• Testosterone → male internal/external genitalia

• AMH → regression of female ducts

Female development

XY females occur because SRY is absent or non-functional.

• Individual has XY chromosomes

• SRY gene is mutated or non-functional

• No functional TDF produced

Development follows the default female pathway

• Gonads are streak gonads (gonadal dysgenesis)

XX males

• During meiosis in the father:

• The SRY gene is mistakenly moved (translocated) from Y → X chromosome

XX but one X chromosome carries SRY so still develops as a make

Chromosomal dosage

because the X chromosomes has many genes that are not present on Y (because Y is smaller and cannot carry as much) , unequal gene dosage can occur between XX female and XY male, which is corrected through X-chromosomeinactivationd

What is dosage compensation

Make sure there is an equal X-linked gene expression, between X chromosomes as females have 2 X chromosomes, there is X inactivation, so only one X chromosomes is functioning and in males there is no inactivation as there is only one X chromosome.

Key features

X inactivation is random, permanent and occurs early (in embryonic development), inactive X becomes a 'Barr body'. All cells will have that same X chromosome deactivated

Why does X need to obe balanced

Unbalanced X = unbalanced proteins = diseas

X codes for many protiens, having too much/little can cause problems. So in females one X is randomly inactivated Barr body

Barr body

A Barr body is a highly condensed inactive X chromosomes found in the nucleoli of somatic cells

Structural abnormalities

Deletion, insertion, duplication, ring chromosome, isochromosome formation check lecture 6 slides)

Ring

isochromosomes

The centromere divides HORIZONTALLY instead of vertically

magine splitting a book:

• One copy gets only chapters 1-5 twice

• Another gets only chapters 6-10 twice

👉 Each copy is missing half the information, even though nothing was "lost overall"

sochromosomes cause duplication of one arm and loss of the other because each resulting chromosome contains only one arm, and cells inherit only one of these abnormal chromosomes.

Inversions

Translocation

Two chromosomes swap segments, chromosomes number usually doesnt change it is rearranged, is no DNA lost then its called a BALANCED translocation

Philadelphia chromosome

Sometimes even if DNA is not lost genes can be distrusted or FUSED the Philadelphia chromosome is reciprocal translocation between chromosomes 9 and 22 that creates the BCR-ABL fusion gene, producing an overactive tyrosine kinase and leading to chronic myeloid leukaemia, no DNA is lost it is functionally unbalanced

if only one X chromosome is active and the Y

chromosome is largely depleted of genes, how can be that

aneuploidy for the sex chromosomes results in any

phenotype at all?

On the X and Y chromosomes there are still PAR regions, the genes are are NOT inactivated and there aree a few other genes on teh non recombining regions of X that are also on the Y. This makes these genes candidates for having gene dosage effects in sex chromosomes

(Although one X chromosome is inactivated, some genes escape inactivation and genes in the pseudoautosomal regions remain active; therefore, changes in sex chromosome number alter gene dosage and result in a phenotype)

Robertsonian translation

A Robertsonian translocation is a special type of translocation involving two acrocentric chromosomes (chromosomes with very short p arms, e.g. 13, 14, 15, 21, 22)

- The long arms (q arms) of two chromosomes fuse at the centromere

• The short arms (p arms) are lost

Because the p arms contain very few important genes (mostly repetitive rRNA gene that exist in multiple copies. No essential genetic information is lost. Problems can arise during meiosis, chromosomes dont separate evenly can produce unbalanced gametes, can make unablanced gametes