Mismatch Repair Genes on Chromosomes 2p and 3p Account for a Major Share of Hereditary Nonpolyposis Colorectal Cancer Families Evaluable by Linkage

Two susceptibility loci for hereditary nonpolyposis colo-rectal cancer (HNPCC) have been identified, and each contains a mismatch repair gene: MSH2 on chromosome 2p and MLH1 on chromosome 3p. We studied the involvement of these loci in 13 large HNPCC kindreds originating from three different continents. Six families showed close linkage to the 2p locus, and a heritable mutation of the MSH2 gene was subsequently found in four. The 2p-linked kindreds included a family characterized by the lack of extracolonic manifestations (Lynch I syndrome), as well as two families with cutaneous manifestations typical of the Muir-Torre syndrome. Four families showed evidence for linkage to the 3p locus, and a heritable mutation of the MLH1 gene was later detected in three. One 3p-linked kindred was of Amerindian origin. Of the remaining three families studied for linkage, one showed lod scores compatible with exclusion of both MSH2 and MLH1, while lod scores obtained in the other two families suggested exclusion of one HNPCC locus (MSH2 or MLH1) but were uninformative for markers flanking the other locus. Our results suggest that mismatch repair genes on 2p and 3p account for a major share of HNPCC in kindreds that can be evaluated by linkage analysis.     

CLINES FOR HYBRID DYSFUNCTION IN A GRASSHOPPER HYBRID ZONE

Two subspecies of the grasshopper Chorthippus parallelus meet in the Pyrenees forming a hybrid zone several kilometers wide. Crosses between the two pure taxa result in sterile male offspring and normal females (i.e., Haldane's rule applies). However, no such dysfunction has been detected in hybrid males collected through the center of the hybrid zone. By assessing the level of dysfunction in the offspring of reciprocal crosses, it was possible to map clines for the genes responsible for dysfunction through the zone. This analysis shows that there is no abrupt transition between incompatible genomes in the field. Crosses were also made between females collected from a transect spanning the hybrid zone and pure males of both subspecies. This reveals noncoincident clines for dysfunction near the center of the hybrid zone such that the dysfunction expressed in the offspring of these crosses is less than expected from simple models. More complex models involving interaction among genes must be invoked. Also, the possibility exists that since the postglacial contact of these two grasshopper taxa, hybrid dysfunction has become ameliorated by the evolution of modifiers. This hybrid zone is thought to be a tension zone, maintained by a balance between selection against hybrid genotypes and dispersal into the zone center. The lessening of hybrid disadvantage over time through the breakdown of epistatic interactions by recombination or through modification could account for the general lack of dysfunction in field collected hybrids today.     

Cloning and characterization of the platypus mitochondrial genome

The vertebrate mitochondrial genome is highly conserved in size and gene content. Among the chordates there appears to be one basic gene arrangement, but rearrangements in the mitochondrial gene order of the avian lineages have indicated that the mitochondrial genome may be more variable than once thought. Different gene orders in marsupials and eutherian mammals leave the ancestral mammalian order in some doubt. We have investigated the mitochondrial gene order in the platypus (Ornithorhynchus anatinus), a representative of the third major group of mammals, to determine which mitochondrial gene arrangement is ancestral in mammals. We have found that the platypus mtDNA conforms to the basic chordate gene arrangement, common to fish, amphibians, and eutherian mammals, indicating that this arrangement was the original mammalian arrangement, and that the unusual rearrangements observed in the avians and marsupials are probably lineage-specific. Correspondence to: N.J. Gemmell     

Relaxation of reproductive suppression in non-breeding female naked mole-rats, Heterocephalus glaber

Ninety-four non-reproductive female naked mole-rats, from seven colonies, were studied in terms of vaginal perforation, vaginal smears and urinary concentrations of oestradiol-17β and progesterone in relation to the time of parturition of the breeding female, the queen. The study concentrated mainly on the period from nine days prepartum to 13 days postpartum of 12 births. Sixty-eight percent ( n = 253) of the non-reproductive females had detectable urinary concentrations of oestradiol-17β and many of these had perforated vaginas throughout the study period. These females showed a significantly increased urinary concentration of oestradiol six days prior to parturition of the queen. In females with undetectable concentrations of oestradiol-17β, the proportion with perforated vaginas increased from six days prepartum (54%) to reach a peak on the day of parturition (92%) of the queen. Urinary progesterone-concentrations were 0.7nmol/mmol creatinine at some stage in the study period in 90% of the females and scattered short peaks or spikes were experienced by all these females, but without synchronization between the females in a colony and without any detectable correlation with the time of parturition of the queen. Maximal concentrations in some females were comparable to the values in cycling breeding females during the luteal phase, but were of a much shorter duration than in breeding females. Vaginal smears did not show clear cyclic patterns.     

rbcL sequences support exclusion ofRetzia,Desfontainia, andNicodemia from theGentianales

The taxonomic positions ofRetzia, Desfontainia, andNicodemia have been much discussed, and all three genera have been included inLoganiaceae (Gentianales). We have made a cladistic analysis ofrbcL gene sequences to determine the relationships of these taxa toGentianales. Four newrbcL sequences are presented; i.e., ofRetzia, Desfontainia, Diervilla (Caprifoliaceae), andEuthystachys (Stilbaceae). Our results show thatRetzia, Desfontainia, andNicodemia are not closely related toLoganiaceae or theGentianales. Retzia is most closely related toEuthystachys and is better included inStilbaceae. The positions ofDesfontainia andNicodemia are not settled, butDesfontainia shows affinity for theDipsacales s.l. andNicodemia for theLamiales s.l.     

Identification of non-catalytic conserved regions in xylanases encoded by the xynB and xynD genes of the cellulolytic rumen anaerobe Ruminococcus flavefaciens

xynB is one of at least four genes from the cellulolytic rumen anaerobe Ruminococcus flavefaciens 17 that encode xylanase activity. The xynB gene is predicted to encode a 781-amino acid product starting with a signal peptide, followed by an amino-terminal xylanase domain which is identical at 89% and 78% of residues, respectively, to the amino-terminal xylanase domains of the bifunctional XynD and XynA enzymes from the same organism. Two separate regions within the carboxy-terminal 537 amino acids of XynB also show close similarities with domain B of XynD. These regions show no significant homology with cellulose- or xylan-binding domains from other species, or with any other sequences, and their functions are unknown. In addition a 30 to 32-residue threonine-rich region is present in both XynD and XynB. Codon usage shows a consistent pattern of bias in the three xylanase genes from R. flavefaciens that have been sequenced.     

Facilitation of Sexual Receptivity by Ventromedial Hypothalamic Implants of the Antiprogestin RU 486

RU 486 is known primarily as an antagonist to progestins and glucocorticoids. However, RU 486 has also been shown to have agonistic progestational properties in biochemical and behavioral studies. In the current study, RU 486 was implanted directly into tim ventromedial hypothalamus (VMH) to test for facilitative action on the receptive behavior of female ovariectomized Long-Evans rats primed with 5 μg of estradiol benzoate. Cannulae containing RU 486, progesterone (P), or empty cannulae were implanted 48 hr after estrogen priming. The lordosis quotient and the lordosis score were assessed 4 hr after the cannulae were lowered by a standardized test consisting of 10 mounts by a stimulus male. P and RU 486 significantly facilitated receptivity compared to blank implants in terms of lordosis quotient and lordosis score, with no significant difference between the hormone treatments. While only a single dose of each treatment was given in the current study, RU 486 facilitated lordosis when implanted to the VMH as well as progesterone in contrast to our previous results where the steroids were administered systemically.