Genetics of sex and the sex chromosome

Question 1

Why does sex matter?

Answer 1

Because it is the fundamental distinction between individuals within a species

Question 2

Give examples of some of the many aspects of genetics that sex affects

Answer 2

Mutation
Recombination
Gene expression
Disease manifestation through sex chromosomes

Question 3

Which sex chromosome is dominantly sex-determining in humans?

Answer 3

Y

Question 4

Which sex chromosome in humans provides the initial genetic switch in the sex determination process?

Answer 4

Y, thereafter sex is determined hormonally

Question 5

What possible rare genotypes could a phenotypic female have?

Answer 5

46, XX (normal)
45, X
47, XXX
48, XXXX
49, XXXXX

Question 6

What possible rare genotypes could a phenotypic male have?

Answer 6

46, XY (normal)
47, XXY
47, XYY
48, XXYY
49, XYYYY

Question 7

The X and Y chromosomes are heteromorphic. True or false?

Answer 7

True

Question 8

Describe the gene content of X

Answer 8

Average (~1000)

Question 9

Describe the gene content of Y

Answer 9

Low (78)

Question 10

Why is the phenotype of a liveborn with an absence of Y (45, X) not as severe when compared with other monosomies?

Answer 10

Because Y bears few genes which are not involved in male-specific development

Question 11

What is the probable mechanism for the expansion of NRY?

Answer 11

Segmental inversion

Question 12

Do the bird Z and W chromosomes have independent origin or not?

Answer 12

Yes, they have independent origin

Question 13

Are there more mutations in males or females?

Answer 13

Males

Question 14

How have disease studies deduced that most mutations come from fathers?

Answer 14

Identified parental origin of new base mutations using linkage

Question 15

Give examples of highly-penetrant dominant diseases passed on from fathers

Answer 15

Achondroplasia, Apert, Pfeiffer or Crouzon syndromes (= craniosynostoses)
MEN2A and -2B (= multiple endocrine neoplasias type 2)

Question 16

Give an example of an extreme disease case in which all mutations occur in males

Answer 16

Achondroplasia (FGFR3 gene)

Question 17

What is the average male to female mutation ratio in disease studies?

Answer 17

~10:1

Question 18

In males there are more cell divisions of the gametes, so this means more of what?

Answer 18

More DNA replications

Question 19

What might explain the male mutation bias and paternal age effect?

Answer 19

If DNA is mutagenic

Question 20

An 80-year-old father has undergone 40x as many replications as a person at what age?

Answer 20

15 years old

Question 21

Describe the recent genome-wide approach to identify base substitutions

Answer 21

Whole genome sequencing
78 parent-offspring trios
Mutations increase with father's age
~2.01 mutations/year
=> paternal mutations double every 16.5 years!

Question 22

Describe the recent genome-wide approach to identify microsatellite mutations

Answer 22

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

Question 23

What is deCODE genetics?

Answer 23

Icelanders
= 1st population Biobank (1996)
Health records and DNA of ~95% present day population
Genealogical records back to 1000 years ago

Question 24

What complex in PAR1 helps to form the XY bivalent in pachytene?

Answer 24

The synaptonemal complex

Question 25

What does PAR1 stand for?

Answer 25

Pseudoautosomal region 1

Question 26

If there is an ancestral relationship between X and Y, you would expect regions of ancestral what?

Answer 26

XY-homology

Question 27

What did Koller and Darlington discover about the sex chromosomes in 1934?

Answer 27

They pair in a specialised region

Question 28

What term did Burgoyne coin in 1982 regarding the sex chromosomes?

Answer 28

'Pseudoautosomal' - partially sex-linked behaviour of loci

Question 29

What gave rise to the strictly homologous PAR1 sequences?

Answer 29

A single obligate recombination event (male meiosis)

Question 30

What no longer commonly occurs in most 47, XXY individuals?

Answer 30

There is no recombination in PAR1

Question 31

What is recombination in PAR1 important for?

Answer 31

The correct segregation of sex chromosomes

Question 32

What is the size of PAR1?

Answer 32

2.7Mb

Question 33

What percentage recombination of PAR1 is there in female meiosis?

Answer 33

7% | ~3-fold over the genome average

Question 34

What percentage recombination of PAR1 is there in male meiosis?

Answer 34

50% | ~20-fold over the genome average

Question 35

What does PAR2 stand for?

Answer 35

Pseudoautosomal region 2

Question 36

What regions of PAR2 sometimes associate to form synaptonemal complexes?

Answer 36

Yqter and Xqter

Question 37

In what year was PAR2 shown molecularly?

Answer 37

1992

Question 38

PAR2 sequences are X-specific in other primates, true or false?

Answer 38

True, e.g. of acquired XY-homology

Question 39

How many genes does the PAR2 region contain?

Answer 39

4

Question 40

What is the size of the PAR2 region?

Answer 40

320kb

Question 41

Is recombination of PAR2 obligate or not?

Answer 41

Not obligate, neither necessary nor sufficient for proper sex chromosome segregation

Question 42

What is the percentage recombination of PAR2?

Answer 42

2% | = 6-fold elevation over the genome average

Question 43

What is the genome average percentage recombination?

Answer 43

1% per Mb OR 1cM per Mb

Question 44

In terms of recombination, which sex chromosome resembles an autosome?

Answer 44

The X in female meiosis

Question 45

What is the genome-wide sex averaged rate of recombination?

Answer 45

1cM per Mb

Question 46

How many times higher is the female recombination rate compared to the male recombination rate?

Answer 46

~1.65 times

Question 47

How many recombination events per meiosis are there in females?

Answer 47

~80

Question 48

How many recombination events per meiosis are there in males?

Answer 48

~50

Question 49

Is the activity of recombination hotspots, i.e. the distribution of recombination, the same or different between males and females?

Answer 49

Different

Question 50

How can you identify recombination 'jungles' and 'deserts'?

Answer 50

By high-density SNP genotyping of ~400,000 SNPS (AffySNP 5.0) of over 2300 meioses

Question 51

What percentage of male and female 'jungles' exist in the 5% most telomeric portion of each chromosome arm?

Answer 51

70% male 'jungles' | 18% female 'jungles'

Question 52

Give a reason why there is a sex difference in recombination on the autosomes

Answer 52

Because females form longer axial elements and have more chromatin loops

Question 53

Describe what happens after a double strand break (DSB) forms at the axis

Answer 53

Homology search and pairing | Crossover, i.e. repair of DSB using homologue

Question 54

The interference distance is the same if measured in microns of synaptonemal complex (SC) but is not the same in..

Answer 54

Megabases

Question 55

Define non-disjunction

Answer 55

The failure of meiotic segregation

Question 56

What is the percentage of aneuploidy in human fertilised eggs when compared with a mouse?

Answer 56

10-30% human | 1-2% mouse

Question 57

What is the leading cause of foetal death in humans, causing ~50% of spontaneous abortions to 15 weeks gestation age?

Answer 57

Aneuploidy

Question 58

When does most gametic aneuploidy originate?

Answer 58

During oogenesis

Question 59

The frequency of non-disjunction errors increases with what?

Answer 59

Female age

Question 60

Trisomy 21 is more commonly known as what disease?

Answer 60

Down syndrome

Question 61

What is the most common autosomal trisomy in liveborns?

Answer 61

Trisomy 21, 1 out of 600

Question 62

Trisomy 21 is usually the result of what type of meiotic error?

Answer 62

Non-disjunction

Question 63

What is the only well documented risk factor for having a child with trisomy 21?

Answer 63

Advanced maternal age

Question 64

What is the most common single cause of mental retardation?

Answer 64

Trisomy 21

Question 65

In human oogenesis, what happens during the 2nd-7th month of gestation?

Answer 65

~1000 oogonia dvide to form ~7E6 germ cells | Then most die - ~2E6

Question 66

In human oogenesis, when does most of meiosis I occur?

Answer 66

During foetal development: synapsis and crossing-over

Question 67

How many oocytes maintained in prolonged diplotene are females born with?

Answer 67

1-2E6

Question 68

When do groups of oocytes periodically resume meiosis?

Answer 68

At the onset of adolescence

Question 69

Segregation during meiosis I and II is delayed until when?

Answer 69

Ovulation and fertilisation

Question 70

How is segregation during meiosis I and II delayed?

Answer 70

Meiosis-specific cohesion complexes released sequentially | => Orderly segregation of homologues and sister chromatids at meiosis I and II respectively

Question 71

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?

Answer 71

'Production line' theory

Question 72

Describe the 'production line' theory

Answer 72

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

Question 73

Why was the 'production line' theory disproven?

Answer 73

Realised that less fit eggs had poorly placed/absent chiasmata

Question 74

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?

Answer 74

'Two-hit' theory

Question 75

Describe the 'two-hit' theory

Answer 75

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

Question 76

How can meiosis I trisomy be distinguished from meiosis II trisomy?

Answer 76

Using centromere markers

Question 77

Give a candidate gene from a mouse model for the age-related 'hit 2'

Answer 77

SMC1beta

Question 78

Give a candidate gene from a yeast model for the age-related 'hit 2'

Answer 78

Shugoshin

Question 79

What are the SMC1beta and shugoshin genes members of and how does this make them candidates for the age-related 'hit 2'?

Answer 79

Members of cohesion complex | Show age-dependent degradation and subsequent premature sister chromatid separation prior to anaphase II

Question 80

Why are cohesions important during development?

Answer 80

Cohesions are loaded onto chromosomes during foetal development Necessary and sufficient to mediate cohesion in the mature oocyte

Question 81

What are the human MAD2 and BUB1 proteins and what is their function?

Answer 81

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

Question 82

What must occur in females due to the presence of two X chromosomes?

Answer 82

Dosage compensation

Question 83

At 7 weeks gestation, are gonadal cells different or indifferent?

Answer 83

Indifferent

Question 84

What type of chromatin allows gene expression?

Answer 84

Euchromatin

Question 85

What are the non-recombining parts of the sex chromosomes known as?

Answer 85

Protosex chromosomes

Question 86

Males have a higher mutation rate which means that the child is more likely to inherit..

Answer 86

A mutation from dad

Question 87

Females have a higher recombination rate which means that the child is more likely to inherit..

Answer 87

Recombination from mum

Question 88

When does female meiosis occur?

Answer 88

All occurs in utero

Question 89

When does male meiosis occur?

Answer 89

From puberty and every year thereafter

Question 90

Do recombination 'jungles' and 'deserts' differ between males and females?

Answer 90

Yes, but not exclusively | Some are hared and some are favoured more than others

Question 91

Where does PRDM9 appear to act?

Answer 91

On chromatin loops