Ovaries and Testes Age in Unique Ways

Ovaries and Testes Age in Unique Ways Tuesday, 03 June 2008 Aging leads to large changes in gene activity in the ovaries of mice, but only limited changes in testes, according to research published in the open-access journal, BMC Biology. A lifespan-extending calorie-restricted diet reversed some of the aging effects – but, unlike the widespread changes observed in somatic organs, it had an impact only in a small number of gonad-specific genes. As well as tackling one of the key questions of ageing – by exploring if reproductive organs age in the same way as other body organs – this research is important in the light of the trend for some women in developed countries to put off childbearing until later in life. A research team led by Minoru Ko, MD, PhD, from the National Institute on Aging, Baltimore, USA used whole-genome DNA microarrays to study the effects of age, sex and diet on the global gene expression in mouse ovaries and testes. They found that reproductive organs age in a different way to other body tissues and, furthermore, that ovaries age in a different way from testes. Age-related changes in gene expression occurred in gonads – as they are known to in other body tissues – but these changes tended to be in different classes of genes. Only two of the six categories of genes previously associated with aging in muscle, kidney and brain were associated with aging in the ovary; none were associated with aging in the testis. The changes seen in ovaries could be influenced by changes in the tissue composition of ovaries as female’s age and ovulation ceases. The researchers also found that calorie restriction in females reduced the expression of genes involved in metabolism and follicle growth, which seems to be consistent with a popular view that the calorie restriction causes a shift in energy use away from reproduction towards general body maintenance and repair. However, male mice on the same diet did not appear to sacrifice reproductive function, suggesting an evolutionary difference between males and females when coping with a food shortage. Reference: Effects of aging and calorie restriction on the global gene expression profiles of testis and ovary Alexei A Sharov, Geppino Falco, Yulan Piao, Suresh Poosala, Kevin G Becker, Alan B Zonderman, Dan L Longo, David Schlessinger and Minoru SH Ko BMC Biology 2008, 6:24, doi:10.1186/1741-7007-6-24 ......... ZenMaster

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Prenatal Screening Misses Half of Chromosomal Abnormalities

Women should be better informed before deciding to undertake it Monday, 02 June 2008 Prenatal biochemical screening tests are widely used to look for chromosomal abnormalities in the foetus which can lead to serious handicap or even death during gestation or in the first few days after birth. But these tests are only able to detect fewer than half of the total chromosomal abnormalities in the foetus, a scientist will tell the annual conference of the European Society of Human Genetics today (Monday 2 June) Dr. Francesca R. Grati, of the TOMA Laboratory, Busto Arsizio, Italy, says that these findings mean that women should be better informed on the limitations of such diagnostic tests. The researchers studied 115,576 prenatal diagnoses carried out during the last fourteen years. 84,847 were amniocenteses, usually carried out around the 16th week of pregnancy, and 30,729 chorionic villus samplings, which can be undertaken from 12 weeks into the pregnancy. Both these tests carry an increased risk of miscarriage, so the decision on whether or not to undertake them can be difficult to weigh up. "Since our sample included a large number of women aged less than 35 who underwent invasive prenatal diagnosis without any pathological indication to do so, we felt that the results could be useful in helping to inform pre-test counselling of such women", says Dr. Grati. "Up until now, the information we had came from smaller studies which only looked at the performance of these tests in detecting a limited number of chromosomal abnormalities." After analysing the results of the chromosomal abnormalities from their own dataset, the researchers combined them with the official detection rates for these abnormalities published by SURUSS and FASTER consortia. These are multi-centre research groups involved in the investigation of screening and diagnostic tests performed in pregnancy, whose results are being used to optimise prenatal care for pregnant patients. They found that current screening procedures were only able to detect half the total chromosomal abnormalities in women both younger and older than 35. The TOMA laboratory is particularly suited to carry out this kind of research, says Dr. Grati, because it was among the first in the world to deal with prenatal diagnosis, and has a vast number of prenatal diagnostic samples at its disposal. Current tests do not detect all foetal chromosomal abnormalities, but only trisomies 21 (Down syndrome), 18 (Edward's syndrome), and 13 (Patau syndrome), monosomy X (Turner syndrome), and triploids (conceptuses with 69 chromosomes instead of 46). "These are common vital chromosomal abnormalities, but there are many others which are not picked up by these tests", says Dr. Grati. "And the tests do not even detect 100% of the common abnormalities." At conception, 23 chromosomes from each parent combine to create a foetus with 46 chromosomes in all its cells. Trisomy occurs when the foetus has one additional chromosome (47 instead 46). The extra genetic material from the additional chromosome causes a range of problems of varying severity. In Down syndrome, for example, where the foetus has three copies of chromosome 21, babies are usually born with impaired cognitive ability and physical growth, cardiac defects and a characteristic facial appearance. Unlike many other such abnormalities, however, babies born with Down syndrome are able to lead relatively normal lives and their life expectancy is around 50 years. Other than trisomy, the foetus can also have the loss of genetic material (deletions) or chromosomal abnormalities in a non-homogeneous form, where there is a mixture of two cell lines, one normal and the other abnormal. "Some of these disorders are relatively common in the foetus, which may have as much chance of surviving as children who are born with Down syndrome, and it is worrying that current biochemical tests are not always able to detect them," says Dr. Grati. "Our research confirms that it is fundamental for doctors to counsel patients about the limitations of current screening methods, so that they can make an informed decision on whether or not to undergo invasive diagnostic testing." ......... ZenMaster

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Genetic Mutation Linked to Walking On All Four

Discovery could help answer basic questions of upright walking Monday, 02 June 2008 What are the genes implicated in upright walking of humans? The discovery of four families in which some members only walk on all fours (quadrupedality) may help us understand how humans, unlike other primates, are able to walk for long periods on only two legs, a scientist will tell the annual conference of the European Society of Human Genetics today (Monday 2 June). The quadrupedal families in Turkey previously attracted attention in 2005, when they were discovered. Now the Turkish team reports that they have found the first gene implicated in quadrupedal locomotion in these families. Professor Tayfun Ozcelik, of Bilkent University, Ankara, Turkey, and colleagues, studied four unrelated families where some members were affected by the rare quadrupedic condition, Unertan syndrome, which is also associated with imperfect articulation of speech, mental retardation, and defects in the cerebellum, a part of the brain involved in motor control. They found that the affected individuals in two families had mutations in the gene responsible for the expression of very low density lipoprotein receptor (VLDLR), a protein which is known to be critical to the proper functioning of the cerebellum during development. Although the families lived in isolated villages 200-300 km apart and reported no ancestral relationships, the scientists expected to find a single genetic mutation implicated in the condition. They were surprised to find that this was not the case. "We carried out genome-wide screening on these families", said Professor Ozcelik, "and found regions of DNA that were shared by all those family members who walk on all fours. However, we were surprised to find that genes on three different chromosomes are responsible for the condition in four different families.” "In families A and D there were mutations in VLDLR on chromosome 9, and in family B the phenotype maps to chromosome 17 to a region that contains at least 157 genes, and we are still looking for the precise mutation. Neither region appears to be implicated for family C." In all cases, the affected individuals were the offspring of consanguineous marriages, which suggests that if they had married outside the family they would not have had the condition. All of them had significant developmental delay in infancy. "Whereas normal infants make the transition to walking on two legs in a relatively short period", said Professor Ozcelik, "these individuals continued to move on their palms and feet and never walked upright. Although they can stand from a sitting position and maintain this upright position with flexed hips and knees, they virtually never initiate bipedal walking on their own." It has been suggested in the past that lack of access to medical care exacerbated the effects of an under-developed cerebellum, and that this led to quadrupedality. "Although it may be true that family B lacked proper medical care, families A and D had consistent access to good medical attention, and both families sought a correction of quadrupedality in their affected children", said Professor Ozcelik. "Indeed, an unaffected member of family A is a physician, who has been actively involved in the medical interventions. In addition, the parents in family A also discouraged their affected children from walking on all fours, to no avail. We think that social factors are unlikely to be involved in the development of quadrupedal locomotion." Mutations causing VLDLR deficiency are also found in Hutterites, a group of Anabaptists who live in colonies of North America. There, however, most of the affected individuals cannot walk at all. The neurological characteristics of the affected members of the Turkish families and the Hutterites seem similar, with the most striking difference being that the Turkish individuals are able to walk on all fours, said the scientists. They hypothesize that the Hutterites may be more profoundly affected due to the deficiency in VLDLR and a neighbouring gene, and therefore lack the motor skills even for quadrupedal locomotion. Along with brain enlargement, speech, and the ability to make tools, upright walking has long been regarded as one of the key traits that have led to modern humans. Professor Ozcelik's team have opened a window on how mutations in VLDLR affect brain development and influence gait in humans. "It will be interesting to see if the VLDLR gene is involved in other types of cerebellar ataxias. In addition, we hope to identify the defective genes associated with quadrupedal locomotion in families B and C", he says. This work was supported through grants from the Scientific and Technological Research Council of Turkey in Ankara, and the International Centre for Genetic Engineering and Biotechnology in Trieste, Italy. Professor Ozcelik and his colleagues are currently screening the remaining families for mutations. ......... ZenMaster

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