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Biomedical subjects

Neil E Lamb

Publications and source records attributed to Neil E Lamb.

6 recordsLinked to original sources
PubMed2005

A new method for identifying informative genetic markers in selectively bred rats.

Microsatellite length polymorphisms are useful for the mapping of heritable traits in rats. Over 4000 such microsatellites have been characterized for 48 inbred rat strains and used successfully to map phenotypes that differ between strains. At present, however, it is difficult to use this microsatellite database for mapping phenotypes in selectively bred rats of unknown genotype derived from outbred populations because it is not immediately obvious which markers might differ between strains and be informative. We predicted that markers represented by many alleles among the known inbred rat strains would also be most likely to differ between selectively bred strains derived from outbred populations. Here we describe the development and successful application of a new genotyping tool (HUMMER) that assigns "heterozygosity" (Het) and "uncertainty" (Unc) scores to each microsatellite marker that corresponds to its degree of heterozygosity among the 48 genotyped inbred strains. We tested the efficiency of HUMMER on two rat strains that were selectively bred from an outbred Sprague-Dawley stock for either high or low activity in the forced swim test (SwHi rats and SwLo rats, respectively). We found that the markers with high Het and Unc scores allowed the efficient selection of markers that differed between SwHi and SwLo rats, while markers with low Het and Unc scores typically identified markers that did not differ between strains. Thus, picking markers based on Het and Unc scores is a valuable method for identifying informative microsatellite markers in selectively bred rodent strains derived from outbred populations.

Animals↗
PubMed2004

Association between maternal age and meiotic recombination for trisomy 21.

Altered genetic recombination has been identified as the first molecular correlate of chromosome nondisjunction in both humans and model organisms. Little evidence has emerged to link maternal age--long recognized as the primary risk factor for nondisjunction--with altered recombination, although some studies have provided hints of such a relationship. To determine whether an association does exist, chromosome 21 recombination patterns were examined in 400 trisomy 21 cases of maternal meiosis I origin, grouped by maternal age. These recombination patterns were used to predict the chromosome 21 exchange patterns established during meiosis I. There was no statistically significant association between age and overall rate of exchange. The placement of meiotic exchange, however, differed significantly among the age groups. Susceptible patterns (pericentromeric and telomeric exchanges) accounted for 34% of all exchanges among the youngest class of women but only 10% of those among the oldest class. The pattern of exchanges among the oldest age group mimicked the pattern observed among normally disjoining chromosomes 21. These results suggest that the greatest risk factor for nondisjunction among younger women is the presence of a susceptible exchange pattern. We hypothesize that environmental and age-related insults accumulate in the ovary as a woman ages, leading to malsegregation of oocytes with stable exchange patterns. It is this risk, due to recombination-independent factors, that would be most influenced by increasing age, leading to the observed maternal age effect.

Adult↗
PubMed2004

Recombination rate and reproductive success in humans.

Intergenerational mixing of DNA through meiotic recombinations of homologous chromosomes during gametogenesis is a major event that generates diversity in the eukaryotic genome. We examined genome-wide microsatellite data for 23,066 individuals, providing information on recombination events of 14,140 maternal and paternal meioses each, and found a positive correlation between maternal recombination counts of an offspring and maternal age. We postulated that the recombination rate of eggs does not increase with maternal age, but that the apparent increase is the consequence of selection. Specifically, a high recombination count increased the chance of a gamete becoming a live birth, and this effect became more pronounced with advancing maternal age. Further support for this hypothesis came from our observation that mothers with high oocyte recombination rate tend to have more children. Hence, not only do recombinations have a role in evolution by yielding diverse combinations of gene variants for natural selection, but they are also under selection themselves.

Adolescent↗
PubMed2004

Identification of Krüppel-like factor 4 as a potential tumor suppressor gene in colorectal cancer.

Krüppel-like factor 4 (KLF4 or GKLF) is an inhibitor of the cell cycle. The gene encoding KLF4 is localized on chromosome 9q, previously shown to exhibit allelic loss in colorectal cancer (CRC). In this study, we show that the mean level of KLF4 mRNA in a panel of 30 CRC was 52% that of paired normal colonic tissues. Similarly, the levels of KLF4 mRNA and protein in a panel of six established CRC cell lines were significantly lower than those of an untransformed colonic epithelial cell line. Using highly polymorphic DNA markers that flank the KLF4 locus, we found evidence for loss of heterozygosity (LOH) in two of eight surgically resected CRC specimens. In addition, LOH was observed in five of six CRC cell lines with one additional cell line exhibiting hemizygous deletion in the KLF4 gene. We also found that the 5'-untranslated region of KLF4 was hypermethylated in a subset of resected CRC specimens and cell lines. Lastly, the open-reading frame of KLF4 in two of three CRC cell lines examined contained several point mutations that resulted in a diminished ability to activate the p21(WAF1/Cip1) promoter. These findings indicate that KLF4 is a potential tumor suppressor gene in CRC.

5' Untranslated Regions↗
PubMed2002

Obligate short-arm exchange in de novo Robertsonian translocation formation influences placement of crossovers in chromosome 21 nondisjunction.

Robertsonian translocations (ROBs) involving chromosome 21 are found in approximately 5% of patients with Down syndrome (DS). The most common nonhomologous ROB in DS is rob(14q21q). Aberrant recombination is associated with nondisjunction (NDJ) leading to trisomy 21. Haplotype analysis of 23 patients with DS and de novo rob(14q21q) showed that all translocations and all nondisjoined chromosomes 21 were maternally derived. Meiosis II NDJ occurred in 21 of 23 families. For these, a ROB DS chromosome 21 genetic map was constructed and compared to a normal female map and a published trisomy 21 map derived from meiosis II NDJ. The location of exchanges differed significantly from both maps, with a significant shift to a more distal interval in the ROB DS map. The shift may perturb segregation, leading to the meiosis II NDJ in this study, and is further evidence for crossover interference. More importantly, because the event in the short arms that forms the de novo ROB influences the placement of chiasmata in the long arm, it is most likely that the translocation formation occurs through a recombination pathway in meiosis. Additionally, we have demonstrated that events that occur in meiosis I can influence events, such as chromatid segregation in meiosis II, many decades later.

Chromosome Aberrations↗