Y chromosome mutations and ICSI; Importance of Y chromosomal and mitochondrial polymorphisms in population genetics

Question 1

infertility facts

Answer 1

can be due to: faillure to conceive, loss of conceptus

origin of problem
35% female
35% male
20% both parters
10% unexplained

Question 2

semen analysis

Answer 2

volume 1.5-5 ml
sperm density >20 million/ml
sperm motility >50%
sperm moprhology 30% normal forms
leukocyte density <1 million/ml

Question 3

teratospermia

Answer 3

sperms have abnormal morphology or appearance

Question 4

etiology of male infertility

Answer 4

Varicocele (35-40%)
Idiopathic (25%)
Infection (~10%)
Genetic (~10%)
Endocrine (<5%) 
Cryptorchidism (<5%) 

Obstruction (<5%)

Immunologic (<5%)

Question 5

varicocele

Answer 5

These dilated scrotal veins are present in 16 percent of all men but are more common in infertile men—40 percent. They impair sperm development by preventing proper drainage of blood. Varicoceles are easily discovered on physical examination since the veins feel distinctively like a bag of worms. They may also be enlarged and twisted enough to be visible in thescrotum. This is the most common correctable cause of male infertility.

Question 6

obstructive azzospermia (OA)
clinical features

Answer 6

Normal testicular volume (>15 ml)
Normal serum levels of FSH, LH, testosterone
Normal or reduced semen volume (obstructive)
CBAVD - congenital bilateral absence of vas deferens
Normal testicular biopsy (normal spermatogenesis)

Question 7

OA etiology

Answer 7

Idiopathic OA 
Iatrogenic OA (hernia repair, orchidopexy)
Infectious (gonorrhea, chlamydia)
Traumatic
Genetic - CF with CBAVD

Question 8

genetics and infertility

Answer 8

Genetics play a central role in fertility, particularly since sperm carry half of the DNA mix to the partner’s egg. Abnormalities inchromosomalnumbers and structure as well as deletions on the importantY chromosomepresent in normal males can also impact fertility

Question 9

non obstructive azoospermia etiology

Answer 9

idiopathic
genetic
testicular torsion
chemo or radiotherapy induced
medicaed
hormonal deficiency (kallmann's syndrome)
anejaculation

Question 10

human sperm DNA characteristics

Answer 10

highly compacted and packaged with protamines
held together by disulfide bonds
10-15% of sperm have DNA damage
sperm DNA can be modifed by endogenous endonucleases

Question 11

what are protamines

Answer 11

small,arginine-rich,nuclearproteinsthat replacehistoneslate in thehaploidphase ofspermatogenesisand are believed essential forspermhead condensation andDNAstabilization.

Question 12

intra-testicular causes for sperm dna damage

Answer 12

protamine P1, P2 deficiency
mutations in the protamine gene cluster

topoisomerase II and transition protein abnormalities (required for repair of induced DNA breaks during super-coiling)

apoptosis

Question 13

post-testicular or external causes for sperm dna damage

Answer 13

febrile illness 
semen oxidants (or ROS) can induce sperm DNA damage 

cause sperm DNA oxidation and fragmentation in vitro

residual sperm cytoplasm correlates with sperm dna damage

Question 14

Genetic causes for infertility

Answer 14

Karyotype analysis
Abnormal karyogram in ~3-5% of infertile men (e.g. inversions or
Klinefelter’s 47 XXY);
1-2% of infertile men (2x DAX)
Y- chromosome micro-deletions
7-10% of infertile men vs. ~2% of fertile men
Cystic Fibrosis (CF) gene mutations
Carrier frequency;
~80% in CBAVD (Congenital absence of the vas deferens) vs. ~30% of infertile vs. ~4% fertile men

Kallmann syndrome

Question 15

MSY

Answer 15

male specific region of Y

99.9% identity

Question 16

two forms of productive recombination in human y chromosome

Answer 16

X-Y crossing-over in pseudoautosomal regions

Y-Y gene conversion in portions of MSY consisting of nearly identical sequence pairs; palindromes

Question 17

MSY components

Answer 17

76 protein coding genes
27 distinct proteins
spermatogenic specialization

gene rich palindormes of unprecedented scale and precision

gene conversion and method of preserving gene integrity?

Question 18

Y chromosome micro-deletions

Answer 18

common cause of male infertility

USP9Y required for sperm production

Question 19

why is there no sperm production in azoospermia

Answer 19

reasons include:
mutations like y deletion
radiotherapy
chemotherapy
mumps orchitis
testicular trauma

the spermatogonia cells cannot device
germ cells divison arrest in late stages

Question 20

ART:

Answer 20

assisted reproduction technology

• compensation for teh impairment of sperm chromatin integity
• transmisison of abnormal genetic material
• current methods for evalulating sperm DNA integrity are not standardized and are not routinely used in clinical laboratories
• to date no treatment for abnormal DNA integirty has proven to be of clinical value

Question 21

DNA, fertilization, and pregnancy

Answer 21

High levels of sperm DNA damage probably do not affect fertilization or early embryo development

May have an effect on pregnancy rates with advanced reproductive technologies (IVF and IVF/ICSI) and recurrent pregnancy loss with spontaneous conception

Question 22

Bechwitth Wiedemann syndrome in ART children

Answer 22

5-10 fold higher incidence
same clinical features
same rate in ICSI vs IVF

Question 23

conclusion of male infertility

Answer 23

Male infertility is multifactorial

Hormones, physiology, environment, anatomy and DNA all play a role

It is the delicate balance of all of these factors that must be weighed in order to optimize male fertility

Every evaluation is different and every treatment strategy is geared toward the individual patient and circumstance and must always take into account the female partner

Question 24

haplotype

Answer 24

a genetic class described by a series of dna sequences or genes (alleles) that are found together in the same physical chromosomes

Question 25

Haplogroup

Answer 25

usually applied to a set of mtDNA or Y chromosomal haplotypes that is defined by relatively slowly mutating markers and that has more phylogenetic stability than other haplotypes

Question 26

the human y-chromosome DNa haplogroup

Answer 26

non-recombining portions of DNA

genetic diversity based on single-nucleotide polymorphisms

Question 27

mitochondrial genome

Answer 27

several thousand copies per cell of dna molecules (polyploidy)

37 genes encoded

exclusively maternal inheritence

all genes on both strands are transcribed as large polycistrons

Question 28

rapid changes in allele frequency can occur in a single generation

Answer 28

partitioning of mdDNA into homoplasmic segregation units

selection of a group of mtDNA molecules to re-populate the next generation