Tuesday, July 29, 2008

Especially for point mutations, expanded simple tandem repeats and structural chromosome mutations, the contribution of the male germline is dominant.

Hum Mol Genet. 2008 Jul 1;17(13):1922-37. Epub 2008 Mar 18.
DNA double-strand break repair in parental chromatin of mouse zygotes, the first cell cycle as an origin of de novo mutation.
Derijck A, van der Heijden G, Giele M, Philippens M, de Boer P.
Department of Obstetrics and Gynaecology, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB, Nijmegen, The Netherlands.
In the human, the contribution of the sexes to the genetic load is dissimilar. Especially for point mutations, expanded simple tandem repeats and structural chromosome mutations, the contribution of the male germline is dominant. Far less is known about the male germ cell stage(s) that are most vulnerable to mutation contraction. For the understanding of de novo mutation induction in the germline, mechanistic insight of DNA repair in the zygote is mandatory. At the onset of embryonic development, the parental chromatin sets occupy one pronucleus (PN) each and DNA repair can be regarded as a maternal trait, depending on proteins and mRNAs provided by the oocyte. Repair of DNA double-strand breaks (DSBs) is executed by non-homologous end joining (NHEJ) and homologous recombination (HR). Differentiated somatic cells often resolve DSBs by NHEJ, whereas embryonic stem cells preferably use HR. We show NHEJ and HR to be both functional during the zygotic cell cycle. NHEJ is already active during replacement of sperm protamines by nucleosomes. The kinetics of G1 repair is influenced by DNA-PK(cs) hypomorphic activity. Both HR and NHEJ are operative in S-phase, HR being more active in the male PN. DNA-PK(cs) deficiency upregulates the HR activity. Both after sperm remodeling and at first mitosis, spontaneous levels of gammaH2AX foci (marker for DSBs) are high. All immunoflurescent indices of DNA damage and DNA repair point at greater spontaneous damage and induced repair activity in paternal chromatin in the zygote.
PMID: 18353795 [PubMed - indexed for MEDLINE]
Related Articles
gammaH2AX signalling during sperm chromatin remodelling in the mouse zygote. [DNA Repair (Amst). 2006]
Mechanisms of DNA double strand break repair and chromosome aberration formation. [Cytogenet Genome Res. 2004]
An xrcc4 defect or Wortmannin stimulates homologous recombination specifically induced by double-strand breaks in mammalian cells. [Nucleic Acids Res. 2002]
Differential H4 acetylation of paternal and maternal chromatin precedes DNA replication and differential transcriptional activity in pronuclei of 1-cell mouse embryos. [Development. 1997]
Ionizing radiation and genetic risks XIV. Potential research directions in the post-genome era based on knowledge of repair of radiation-induced DNA double-strand breaks in mammalian somatic cells and the origin of deletions associated with human genomic disorders. [Mutat Res. 2005]

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Tuesday, July 15, 2008

A Must see Video

Male Biological Clock How Single Gene Disorders that are De Novo/ non-familial/sporadic come into being


Monday, July 7, 2008

Man's Ability to Have Kids is Dependent on His Age Written by Theresa Maher

Excellent Article by Theresa Maher!

Written by Theresa Maher

MONDAY, July 7, (News Locale) - Contrary to popular perception, a man is not able to have kids anytime he wishes. New research out of France indicates male fertility is also dependent on age and men who delay fatherhood may have a tough time conceiving later on

It is believed that unlike women, men have no biological clock and can father children throughout their life. In fact it is not uncommon to see celebrities having babies well after they have crossed their 50s.

Now researchers at the Eylau Centre for Assisted Reproduction in Paris have revealed men who delay fatherhood have a less chance of impregnating their partners.

The study of more than 20,000 couples who sought fertility help at the center found men over the age of 35 are almost a third less likely to conceive as compared to their younger counterparts. Furthermore men over the age of 40 had poor quality of sperm, which could lead to frequent miscarriages in their partners. In fact the risk of miscarriage if the father was over the age of 40 was 75 percent.

Researchers believe the DNA in sperm starts to decay with age and this may be the cause of fertility issues in older men.

The details of the study were presented at the European Society of Human Reproduction and Embryology conference.

An earlier study by Danish researchers had revealed kids born to older fathers were more likely to die before they entered adulthood when compared to kids born to younger fathers. This incidence was attributed to the declining quality of sperm due to ageing.

The scientists found that congenital defects like heart and spine problems were the main cause of death in these children.

Additionally the risk of autism, epilepsy or schizophrenia also increased in these kids, which led to accidental deaths as well, the researchers had reported in the European Journal of Epidemiology.

Consumers must be aware that the mother's age has always been associated with pregnancy complications. The above study provides evidence that a father's age may also have a say in conception.

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Sunday, July 6, 2008

Men's fertility decreases after 35, study confirms

Men's fertility decreases after 35, study confirms
Kate Benson Medical Reporter
July 7, 2008

IT HAS long been known that a woman's chance of reproducing declines once she hits 35, but now scientists have found that men who have some forms of fertility treatment in their 30s suffer the same fate.
A study by Laboratoire d'Eylau, a centre for assisted reproduction in Paris, followed more than 21,000 men who had intrauterine inseminations at fertility clinics. It found the process, where semen is washed to extract the sperm, resulted in a decrease in pregnancies and an increase in miscarriages.

All the men in the study, which will be presented today at the annual conference of the European Society for Human Reproduction and Embryology, were aged over 35.

"We already believed that couples where the man was older took longer to conceive," said the study's author, Stephanie Belloc.

"But how DNA damage in older men translates into clinical practice has not been shown up to now. Our research shows for the first time that there is a strong paternal age-related affect on [intrauterine insemination] outcomes and this information should be considered by both doctors and patients in assisted reproduction."

She said sperm with DNA damage, common in older men, could still enter the egg during intrauterine insemination, which could result in a failure to conceive or a miscarriage.

But during in vitro fertilisation, the zona pellucida, or outer membrane of the egg, was an efficient barrier in preventing the penetration of sperm with DNA damage.

"And in ICSI [intracytoplasmic sperm injection], the best sperm can be selected for use. These methods, although not in themselves a guarantee of success, may help couples where the man is older to achieve a pregnancy more quickly and reduce the risk of miscarriage," Dr Belloc said.

She followed 21,239 patients, and examined the sperm of each partner for count, motility and morphology. Pregnancy rates, miscarriage and delivery rates were also recorded.

"Some recent studies have established a relationship between the results of [intrauterine insemination] and DNA damage, which also correlated to a man's age, suggesting it might be an important factor, but until now there was no clinical proof. We have now found that the age of the father was important in pregnancy - men over 35 had a negative effect."

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