Genetics of sex and the sex chromosome Flashcards
Why does sex matter?
Because it is the fundamental distinction between individuals within a species
Give examples of some of the many aspects of genetics that sex affects
Mutation
Recombination
Gene expression
Disease manifestation through sex chromosomes
Which sex chromosome is dominantly sex-determining in humans?
Y
Which sex chromosome in humans provides the initial genetic switch in the sex determination process?
Y, thereafter sex is determined hormonally
What possible rare genotypes could a phenotypic female have?
46, XX (normal) 45, X 47, XXX 48, XXXX 49, XXXXX
What possible rare genotypes could a phenotypic male have?
46, XY (normal) 47, XXY 47, XYY 48, XXYY 49, XYYYY
The X and Y chromosomes are heteromorphic. True or false?
True
Describe the gene content of X
Average (~1000)
Describe the gene content of Y
Low (78)
Why is the phenotype of a liveborn with an absence of Y (45, X) not as severe when compared with other monosomies?
Because Y bears few genes which are not involved in male-specific development
What is the probable mechanism for the expansion of NRY?
Segmental inversion
Do the bird Z and W chromosomes have independent origin or not?
Yes, they have independent origin
Are there more mutations in males or females?
Males
How have disease studies deduced that most mutations come from fathers?
Identified parental origin of new base mutations using linkage
Give examples of highly-penetrant dominant diseases passed on from fathers
Achondroplasia, Apert, Pfeiffer or Crouzon syndromes (= craniosynostoses)
MEN2A and -2B (= multiple endocrine neoplasias type 2)
Give an example of an extreme disease case in which all mutations occur in males
Achondroplasia (FGFR3 gene)
What is the average male to female mutation ratio in disease studies?
~10:1
In males there are more cell divisions of the gametes, so this means more of what?
More DNA replications
What might explain the male mutation bias and paternal age effect?
If DNA is mutagenic
An 80-year-old father has undergone 40x as many replications as a person at what age?
15 years old
Describe the recent genome-wide approach to identify base substitutions
Whole genome sequencing 78 parent-offspring trios Mutations increase with father's age ~2.01 mutations/year => paternal mutations double every 16.5 years!
Describe the recent genome-wide approach to identify microsatellite mutations
2477 loci in 24832 trios 2058 inherited mutations 3:1 male bias Rate in fathers doubles from 20-58 years! Longer alleles are more mutagenic
What is deCODE genetics?
Icelanders
= 1st population Biobank (1996)
Health records and DNA of ~95% present day population
Genealogical records back to 1000 years ago
What complex in PAR1 helps to form the XY bivalent in pachytene?
The synaptonemal complex
What does PAR1 stand for?
Pseudoautosomal region 1
If there is an ancestral relationship between X and Y, you would expect regions of ancestral what?
XY-homology
What did Koller and Darlington discover about the sex chromosomes in 1934?
They pair in a specialised region
What term did Burgoyne coin in 1982 regarding the sex chromosomes?
‘Pseudoautosomal’ - partially sex-linked behaviour of loci
What gave rise to the strictly homologous PAR1 sequences?
A single obligate recombination event (male meiosis)
What no longer commonly occurs in most 47, XXY individuals?
There is no recombination in PAR1
What is recombination in PAR1 important for?
The correct segregation of sex chromosomes
What is the size of PAR1?
2.7Mb
What percentage recombination of PAR1 is there in female meiosis?
7%
~3-fold over the genome average
What percentage recombination of PAR1 is there in male meiosis?
50%
~20-fold over the genome average
What does PAR2 stand for?
Pseudoautosomal region 2
What regions of PAR2 sometimes associate to form synaptonemal complexes?
Yqter and Xqter
In what year was PAR2 shown molecularly?
1992
PAR2 sequences are X-specific in other primates, true or false?
True, e.g. of acquired XY-homology
How many genes does the PAR2 region contain?
4
What is the size of the PAR2 region?
320kb
Is recombination of PAR2 obligate or not?
Not obligate, neither necessary nor sufficient for proper sex chromosome segregation
What is the percentage recombination of PAR2?
2%
= 6-fold elevation over the genome average
What is the genome average percentage recombination?
1% per Mb
OR
1cM per Mb
In terms of recombination, which sex chromosome resembles an autosome?
The X in female meiosis
What is the genome-wide sex averaged rate of recombination?
1cM per Mb
How many times higher is the female recombination rate compared to the male recombination rate?
~1.65 times
How many recombination events per meiosis are there in females?
~80
How many recombination events per meiosis are there in males?
~50
Is the activity of recombination hotspots, i.e. the distribution of recombination, the same or different between males and females?
Different
How can you identify recombination ‘jungles’ and ‘deserts’?
By high-density SNP genotyping of ~400,000 SNPS (AffySNP 5.0) of over 2300 meioses
What percentage of male and female ‘jungles’ exist in the 5% most telomeric portion of each chromosome arm?
70% male ‘jungles’
18% female ‘jungles’
Give a reason why there is a sex difference in recombination on the autosomes
Because females form longer axial elements and have more chromatin loops
Describe what happens after a double strand break (DSB) forms at the axis
Homology search and pairing
Crossover, i.e. repair of DSB using homologue
The interference distance is the same if measured in microns of synaptonemal complex (SC) but is not the same in..
Megabases
Define non-disjunction
The failure of meiotic segregation
What is the percentage of aneuploidy in human fertilised eggs when compared with a mouse?
10-30% human
1-2% mouse
What is the leading cause of foetal death in humans, causing ~50% of spontaneous abortions to 15 weeks gestation age?
Aneuploidy
When does most gametic aneuploidy originate?
During oogenesis
The frequency of non-disjunction errors increases with what?
Female age
Trisomy 21 is more commonly known as what disease?
Down syndrome
What is the most common autosomal trisomy in liveborns?
Trisomy 21, 1 out of 600
Trisomy 21 is usually the result of what type of meiotic error?
Non-disjunction
What is the only well documented risk factor for having a child with trisomy 21?
Advanced maternal age
What is the most common single cause of mental retardation?
Trisomy 21
In human oogenesis, what happens during the 2nd-7th month of gestation?
~1000 oogonia dvide to form ~7E6 germ cells
Then most die - ~2E6
In human oogenesis, when does most of meiosis I occur?
During foetal development: synapsis and crossing-over
How many oocytes maintained in prolonged diplotene are females born with?
1-2E6
When do groups of oocytes periodically resume meiosis?
At the onset of adolescence
Segregation during meiosis I and II is delayed until when?
Ovulation and fertilisation
How is segregation during meiosis I and II delayed?
Meiosis-specific cohesion complexes released sequentially
=> Orderly segregation of homologues and sister chromatids at meiosis I and II respectively
What is the theory called (postulated by Henderson and Edwards in 1968) that was originally thought to explain why aging human oocytes are prone to aneuploidy?
‘Production line’ theory
Describe the ‘production line’ theory
Occytes that are first produced by the foetus are more fit and the first to be ovulated
As a woman approaches menopause, she has more ‘bad’ eggs
Why was the ‘production line’ theory disproven?
Realised that less fit eggs had poorly placed/absent chiasmata
What is the theory called (postulated by Hawley et al. in 1996) that is now thought to explain why aging human oocytes are prone to aneuploidy?
‘Two-hit’ theory
Describe the ‘two-hit’ theory
Hit 1 = diminished recombination (caused by lack of or misplaced chiasma) produces ‘susceptible’ chromosomes
Hit 2 = eg. reduction in ability of meiosis molecular machinery with increasing age
How can meiosis I trisomy be distinguished from meiosis II trisomy?
Using centromere markers
Give a candidate gene from a mouse model for the age-related ‘hit 2’
SMC1beta
Give a candidate gene from a yeast model for the age-related ‘hit 2’
Shugoshin
What are the SMC1beta and shugoshin genes members of and how does this make them candidates for the age-related ‘hit 2’?
Members of cohesion complex
Show age-dependent degradation and subsequent premature sister chromatid separation prior to anaphase II
Why are cohesions important during development?
Cohesions are loaded onto chromosomes during foetal development
Necessary and sufficient to mediate cohesion in the mature oocyte
What are the human MAD2 and BUB1 proteins and what is their function?
Conserved kinetochore-associated proteins
RT-PCR found that the concentration of transcripts decreases as human oocytes age
Involved in the regulation of progression from metaphase to anaphase
What must occur in females due to the presence of two X chromosomes?
Dosage compensation
At 7 weeks gestation, are gonadal cells different or indifferent?
Indifferent
What type of chromatin allows gene expression?
Euchromatin
What are the non-recombining parts of the sex chromosomes known as?
Protosex chromosomes
Males have a higher mutation rate which means that the child is more likely to inherit..
A mutation from dad
Females have a higher recombination rate which means that the child is more likely to inherit..
Recombination from mum
When does female meiosis occur?
All occurs in utero
When does male meiosis occur?
From puberty and every year thereafter
Do recombination ‘jungles’ and ‘deserts’ differ between males and females?
Yes, but not exclusively
Some are hared and some are favoured more than others
Where does PRDM9 appear to act?
On chromatin loops
