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PubMed2001

Reproductive ecology and life history of the human male.

Until recently, the reproductive ecology of human males has not been extensively investigated, primarily as a result of the need for a theoretical framework based on the reproductive constraints and energetics of mammalian males. More specifically, male reproductive ecology has necessitated an integrative interpretation of clinical and anthropological data based on the premise that the evolution of human male life histories has involved selection for physiological mechanisms aimed at optimizing trade-offs between survivorship and reproductive effort. This paper attempts to address this gap in our understanding by presenting the current state of male reproductive ecology, including physiologic data from clinical and anthropological investigations as well as recent theoretical developments. Recent investigations outlining population variation in reproductive endocrine function are discussed within the context of potential sources of variation, including energetic expediture, caloric intake, and developmental canalization during adolescence. Additional summaries of male senescence and behavior are presented to provide a complete overview of male life history. Implications of recent anthropological data on contemporary health issues such as prostate cancer and the development of a male contraceptive are also discussed. Finally, several theories are presented that may contribute to our understanding of the evolution of male life histories and reproductive ecology, including theoretical suggestions involving the role of competition, mate choosiness, and potential constraints on male insemination ability, as well as a theory suggesting that male reproductive ecology may be best understood by analyzing energetic allocation decisions between differing somatic tissues that may be indicative of the competing needs for optimizing survivorship and reproductive effort. Directions for future research are finally considered.

Aging↗
PubMed2025

Biochemical assays for AID/APOBECs and the identification of AID/APOBEC inhibitors.

Activation-induced cytidine deaminase (AID) and apolipoprotein B-mRNA editing catalytic polypeptide 3 (APOBEC3 or A3) proteins belong to the AID/APOBEC family of cytidine deaminases. While AID mediates somatic hypermutation and class-switch recombination in adaptive immunity, A3s restrict viruses and retroelements by hypermutation. Mis-regulated expression and off-target activity of AID/A3 can cause genome-wide mutations promoting oncogenesis, immune evasion, and therapeutic resistance due to tumor and viral evolution. In these contexts, inhibition of AID/A3 represents a promising therapeutic approach. Competitive inhibition could be achieved with different strategies: one class would be small molecules that bind in the catalytic pocket (active site) and block access for the substrate cytidine. Another type of larger molecule inhibitor would bind the enzymes' surface more broadly and compete with the binding of the polynucleotide substrates prior to deamination catalysis. Several biochemical assays developed to assess AID/A3 activity can be employed to screen for potential inhibitors. These include in cellulo and in vitro activity-based as well as binding-based assays. In this chapter, we discuss the key considerations for designing robust enzyme assays and provide an overview of assays that we and others have established or modified for specific applications in AID/A3 enzymology, including measurement of inhibition. We provide detailed protocols for the two most widely used in vitro enzyme assays that directly measure the activities of purified AID/A3s on DNA and/or RNA substrates, namely, the gel-based alkaline cleavage assay and multiple variations of PCR/sequencing-based assays.

Cytidine Deaminase↗
PubMed1995

Effects of axotomy, deafferentation, and reinnervation on sympathetic ganglionic synapses: a comparative study.

The main physiological and morphological features of the synapses in the superior cervical ganglia of mammals and the last two abdominal ganglia of the frog sympathetic chain are summarized. The effects of axotomy on structure and function of ganglionic synapses are then reviewed, as well as various changes in neuronal metabolism in mammals and in the frog, in which the parallel between electrophysiological and morphological data leads to the conclusion that a certain amount of synaptic transmission occurs at "simple contacts." The effects of deafferentation on synaptic transmission and ultrastructure in the mammalian ganglia are reviewed: most synapses disappear, but a number of postsynaptic thickenings remain unchanged. Moreover, intrinsic synapses persist after total deafferentation and their number is strongly increased if axotomy is added to deafferentation. In the frog ganglia, the physiological and morphological evolution of synaptic areas is comparable to that of mammals, but no intrinsic synapses are observed. The reinnervation of deafferented sympathetic ganglia by foreign nerves, motor or sensory, is reported in mammals, with different degrees of efficiency. In the frog, the reinnervation of sympathetic ganglia with somatic motor nerve fibers is obtained in only 20% of the operated animals. The possible reasons for the high specificity of ganglionic connections in the frog are discussed.

Afferent Pathways↗
PubMed1989

Human pepsinogen C (progastricsin). Isolation of cDNA clones, localization to chromosome 6, and sequence homology with pepsinogen A.

The entire pepsinogen C (PGC) coding sequence was determined by analysis of a series of five overlapping cDNA clones identified in a library constructed from human gastric mucosa poly(A+) RNA. A partial cDNA clone was initially identified using a 256-fold degenerate oligonucleotide probe for amino acid residues 4-12 of pepsin C, and subsequently 4 additional clones were identified upon rescreening with a probe complementary to the 5' region of the original cDNA clone. Northern analysis of gastric mucosa poly(A+) RNA with a PGC cDNA probe revealed an mRNA 1.5-kilobase species that was indistinguishable from that detected with a human pepsinogen A (PGA) cDNA probe. In contrast, the PGC and PGA cDNA probes detected distinct genomic restriction fragments indicating there was no detectable cross-hybridization under high stringency conditions. The PGC gene was localized to human chromosome 6 by analysis of a panel of human x mouse somatic cell hybrids. The regions containing the active site aspartyl groups of PGC are conserved in relationship to several other aspartic proteinases. We propose that the absence of detectable immunologic cross-reactivity between the two groups of human pepsinogens, A and C, results from divergent evolution of sequences located on the surface of the zymogens in contrast to the strongly conserved active site regions located within the binding cleft of the enzymes that are inaccessible for antigenic recognition.

Amino Acid Sequence↗
PubMed1999

Primate evolution of an olfactory receptor cluster: diversification by gene conversion and recent emergence of pseudogenes.

The olfactory receptor (OR) subgenome harbors the largest known gene family in mammals, disposed in clusters on numerous chromosomes. We have carried out a comparative evolutionary analysis of the best characterized genomic OR gene cluster, on human chromosome 17p13. Fifteen orthologs from chimpanzee (localized to chromosome 19p15), as well as key OR counterparts from other primates, have been identified and sequenced. Comparison among orthologs and paralogs revealed a multiplicity of gene conversion events, which occurred exclusively within OR subfamilies. These appear to lead to segment shuffling in the odorant binding site, an evolutionary process reminiscent of somatic combinatorial diversification in the immune system. We also demonstrate that the functional mammalian OR repertoire has undergone a rapid decline in the past 10 million years: while for the common ancestor of all great apes an intact OR cluster is inferred, in present-day humans and great apes the cluster includes nearly 40% pseudogenes.

Animals↗
PubMed1975

Q-, C-, and G-banding patterns in the germ-line and somatic chromosomes of Miastor sp. (Diptera: Cecidomyidae).

Q-, C-, and G-banding patterns are described for the germ-line and somatic chromosomes of Miastor sp. The chromosome number in the germ line is 36, which is 3 less than that previously reported for the same cultured line 18 years ago. There are 8 chromosome groups: 8 large acrocentrics, 11 large and medium submetacentrics, 4 medium metacentrics, 4 medium subtelocentrics, 6 medium telocentrics, one medium acrocentric, one small submetacentric, and one small telocentric. All 8 large acrocentrics have a Q-band and an interstitial C-band in the short arm, suggesting that these chromosomes are at least partially homologous (or homeologous) and that the germ line originally was polyploid. Only one other germ-line chromosome, the small submetacentric, has a Q-band and an interstitial C-band. In somatic cells there are 8 chromosomes, 28 chromosomes having been eliminated during early cleavage. Three of the four pairs of somatic chromosomes are heteromorphic, despite the indications of a polyploid origin of the germ-line chromosomes and despite the presence of somatic pairing. Furthermore, there is a great deal of restriction on which chromosomes are retained in somatic cells, and it may be that the same 8 chromosomes are retained by all embryos. The G-banding pattern is not as clear as the other two banding patterns. The findings are discussed in relation to observations in other cecidomyids, and a model for the evolution of the chromosome system of Miastor is presented.

Animals↗
PubMed1992

X inactivation in mammalian testis is correlated with inactive X-specific transcription.

X chromosome inactivation occurs twice during the mammalian life cycle. In females one of the two X chromosomes of somatic nuclei is inactive, while in males the solitary X chromosome is inactivated during germ cell development. Despite the different properties of the inactivated chromosomes of females and males, the molecular initiation of inactivation may be the same. X inactive-specific transcripts, XIST, are produced from somatic inactivated X chromosomes. We demonstrate here the existence of XIST transcripts in testes of man and mouse. Inactivation of X chromosomes in males, as in females, may thus be mediated through XIST. Conceivably, the silencing of X-linked genes is the price paid for the evolution of successful mechanisms of chromosomal sex determination.

Animals↗
PubMed2005

Genes specifically expressed in sexually differentiated female spheroids of Volvox carteri.

Volvox carteri is a multicellular green alga with only two cell types, somatic cells and reproductive cells. Phylogenetic analysis suggests that this organism has evolved from a Chlamydomonas-like unicellular ancestor along with multicellularity, cellular differentiation, and a change in the mode of sexual reproduction from isogamy to oogamy. To examine the mechanism of sexual differentiation and the evolution of oogamy, we isolated 6 different cDNA sequences specifically expressed in sexually differentiated female spheroids. The genes for the cDNAs were designated SEF1 to SEF6. The time course of accumulation of each mRNA was shown to be distinct. The expression of some of these genes was not significantly affected when the sexual inducer was removed after the induction of sexual development. Sequence analysis indicates that SEF5 and SEF6 encode pherophorin-related proteins. Of these, SEF5 has the unique structural feature of a polyproline stretch in the C-terminal domain in addition to the one found in the central region.

Amino Acid Sequence↗
PubMed2001

Somatic hypermutation and B-cell lymphoma.

During the B-cell response to T-cell-dependent antigens, the B cells undergo a rapid proliferative phase in the germinal centre. This is accompanied by the introduction of mutations into the immunoglobulin (Ig) variable region (V) genes. The B cells are then selected according to the affinity of the encoded immunoglobulin for antigen, resulting in affinity maturation of the response. Analysis of mutations in IgV genes has given insight into the history of individual B cells and their malignancies. In most cases, analysis of mutations confirms classifications of B-cell lineage designated by studies of cellular morphology and surface antigen expression. However, of particular interest is the subdivision of groups of malignancies by analysis of somatic hypermutation. It is now apparent that there are two subsets of chronic lymphocytic leukaemia (CLL), one with a low load of mutations and poor prognosis. and one with a heavy load of mutations with a much more favourable prognosis. In addition, in Burkitt's lymphoma, sporadic and endemic subtypes are now considered possibly to have a different pathogenesis, reflected in differences in the numbers of mutations. Hodgkin's disease, which was a mystery for many years, has now been shown to be a B-cell tumour. Although in many cases the Ig genes are crippled by somatic hypermutation, it is thought that failure to express Ig is more likely to be associated with problems of transcription. It has been proposed that the distribution of mutations in a B-cell lymphoma can be used to determine whether a lymphoma is selected. We have investigated the load and distribution of mutations in one group of lymphomas--marginal zone B-cell lymphomas of mucosa-associated lymphoid tissues (MALT-type lymphoma), which are dependent on Helicobacter pylori for disease progression, to investigate the limits of information that can be derived from such studies. Comparison of the load of mutations demonstrates that these tumours have approximately the same load of mutations as normal mucosal marginal zone B cells from the Peyer's patches and mucosal plasma cells. This is consistent with the origin of these cells from mucosal marginal zone B cells with plasma cell differentiation. To investigate selection in MALT lymphomas we compared a region of the framework region three in ten MALT lymphomas which use the V(H4) family, with the same codons in groups of V(H4) genes that are out of frame between V and J. The latter accumulate mutations but are not used and are not selected. A group of V(H4) genes are in-frame between V and J were also included for comparison. There were no obvious differences in the distribution of mutations between the groups of genes; the same hot spots and cold spots were apparent in each. In the MALT lymphomas, selection was apparent in the framework regions only and the tendency was to conserve. We therefore feel that there is selection to conserve antibody structure and that this does not reflect selection for antigen. We do not believe that antigen selection can be deduced reliably from sequence information alone. It is possible that somatic hypermutation could be a cause of malignancy since it has been shown that the process may generate DNA strand breaks and is known to be able to generate insertions and deletions. Such events may mediate the translocation of genes--a process that is pivotal in the evolution of many lymphomas.

Antigens↗
PubMed1994

Genomic organization and chromosomal localization of a novel human hepatic dihydrodiol dehydrogenase with high affinity bile acid binding.

We previously characterized and cloned a unique human hepatic dihydrodiol dehydrogenase (DDH) that exhibits high affinity binding for bile acids (Stolz, A., Hammond, L., Lou, H., Takikawa, H., Ronk, M., and Shively, J. E. (1993) J. Biol. Chem. 268, 10448-10457). This hepatic dihydrodiol dehydrogenase demonstrates significant sequence homology with the cytosolic rat bile acid binder 3 alpha-hydroxysteroid dehydrogenase and other members of the monomeric oxidoreductase gene family. We now report the genomic organization and chromosomal localization of the human hepatic DDH in order to further define its physiological role and provide additional insight into the development of this gene family. The 15-kilobase human hepatic DDH gene was contained in an overlapping cosmid and lambda genomic clones and is composed of nine exons. A major transcriptional start site was determined to be 30 base pairs upstream from the ATG initiation methionine by both primer extension and S1 nuclease mapping studies. The human hepatic DDH gene was mapped by chromosomal in situ hybridization and analysis of human-mouse somatic cell hybrids to the tip of the short arm of chromosome 10 at p14. Strict conservation of the intron-exon junctions in the human hepatic DDH and two other members of the monomeric oxidoreductase gene family, aldose reductase and mouse major vas deferens protein suggests evolution from a common ancestral gene. Human hepatic DDH mRNA was identified in both human hepatoma Hep G2 and human lung carcinoma cell line NCI-H322 by RN'ase protection; thus, these cell lines will be useful in examining the regulation of the gene.

Alcohol Oxidoreductases↗
PubMed2002

Differential lipid biosynthesis underlies a tradeoff between reproduction and flight capability in a wing-polymorphic cricket.

The biochemical basis of life-history tradeoffs is a poorly studied aspect of life-history evolution. We used radiotracer and endocrine approaches to investigate the extent to which morphs of a wing-polymorphic insect differ in the biosynthesis of lipid classes important for dispersal capability vs. reproduction (ovarian growth). The flight-capable genotype of Gryllus firmus biosynthesized a greater amount of total lipid and triglyceride (main flight fuel), which was preferentially allocated to somatic tissue during early adulthood. By contrast, the flightless genotype biosynthesized a significantly greater amount of phospholipid (important in egg development), which was preferentially allocated to ovaries. Topical application of a juvenile-hormone mimic to the flight-capable morph caused it to express all aspects of lipid metabolism seen in the flightless morph. Differences in biosynthesis between morphs (i) occur coincident with 100-400% greater ovarian growth in the flightless morph, (ii) result from alterations of both de novo biosynthesis of fatty acid and downstream partitioning of fatty acids into triglyceride vs. phospholipid, and (iii) possibly result from genetically polymorphic hormonal regulators with negative pleiotropic effects on lipid biosynthesis and ovarian growth. The present study provides direct documentation of genetically based alterations of in vivo flux through pathways of intermediary metabolism leading to the differential production of end products central to the specialization of phenotypes for alternate life histories.

Animals↗
PubMed1997

RET Proto-Oncogene and Thyroid Cancer.

The RET proto-oncogene has not only conclusively been identified as responsible for the three subtypes of the inherited cancer syndrome multiple endocrine neoplasia type 2 (MEN-2) but also shown to be involved in the molecular evolution of sporadic medullary and papillary thyroid carcinoma as well as Hirschsprung's disease. A variety of recent studies have elucidated the pathophysiological mechanisms leading to neoplastic disease and we now understand that dominant activating germline mutations lead to MEN-2A, MEN-2B, and familial MTC; somatic mutations to sporadic medullary thyroid carcinoma; RET rearrangements to papillary thyroid carcinoma; and inactivating alterations to Hirschsprung's disease. The clinical significance, however, of RET alterations especially in sporadic thyroid tumors is still controversial and therapeutic concepts in MEN-2 gene carriers only start to emerge. This article is a short summary of the recent findings on the structure and physiology of the RET proto-oncogene and its role in familial and sporadic thyroid cancer.

Journal Article↗
PubMed1986

The medial frontal cortex and gastric motility: microstimulation results and their possible significance for the overall pattern of organization of rat frontal and parietal cortex.

Bilateral intracortical microstimulation (60-90 strains of 0.5 ms pulses at 10 Hz, currents below 50 microA) of medial frontal infralimbic and prelimbic cortical areas in ketamine-anesthetized rats produces clear and consistent decreases in ongoing gastric motility. The majority of responses consists of reductions in gastric tone, reductions in the amplitude of gastric contractions, or combined reductions in tone and amplitude. Bilateral section of the vagus nerves eliminates most of the responses, suggesting that the responses are mediated by this nerve. The effective cortical stimulation zone (the 'visceral motor' cortex) largely overlaps the source of the recently described direct projection from medial frontal cortex to the nucleus of the solitary tract; this pathway may be involved in producing the effect. Connections of this cortex with the limbic system suggest it may be involved in producing physiological responses to stress. The topographical, medial to lateral sequence of cortical functional areas revealed by these and other experiments (visceral motor, frontal eye fields, somatic motor, somatic sensory, visceral sensory) is discussed, as well as the possible implications of this pattern to the question of cortical evolutionary development.

Animals↗
PubMed1980

Lack of heterogeneity in antihapten antibodies of a phylogenetically primitive shark.

Individual mammals have the capacity to express at least one million distinct antigen binding specificities, implying a high degree of structural heterogeneity in the variable heavy and light chain (VH and VL) portions of the antibody molecules. Studies of higher vertebrate species suggest that this heterogeneity is created both through a sizeable repertoire of germ-line VH and VL genes and through random rearrangements of V and joining genes. Additional somatic mechanisms probably also contribute to the ultimate heterogeneity; one-third of murine plasmacytomas producing lambda 1 immunoglobulin carry a somatically mutated Ig1-V gene. The relative contributions of these various mechanisms to the overall imunoglobulin variability are difficult to evaluate. The production of different antibodies to a defined determinant in different individuals of an inbred mouse strain [for example, (3-iodo-4-hydroxy-5-nitrophenyl) acetyl (NIP) in CBA mice] suggests the involvement of somatic mutations or rearrangement but does not rule out the possibility that each individual CBA mouse expresses only a small random fraction from a large germ-line repertoire of V genes determining different anti-NIP binding sites. The opposite finding, that different individuals produce nearly identical antibodies to a defined determinant, would suggest the presence and expression of a limited number of germ-line genes without somatic alterations. Data presented here suggest that primitive sharks (Heterodontus fransisci) produce such antibodies to the hapten furyloxazolone.

Animals↗
PubMed1992

Missense mutations and evolutionary conserved amino acids at the human hypoxanthine phosphoribosyl-transferase locus.

Molecular characterization of in vivo mutation at the human hypoxanthine phosphoribosyltransferase (hprt) locus has revealed a broad spectrum of mutation, both with regard to germ-line mutation in Lesch-Nyhan and gout patients, and somatic mutation in 6-thioguanine resistant T-lymphocytes from healthy individuals. The pattern of missense mutation shows a non-random distribution with a preferential location to codons for amino acids which are identical in human and the two parasites Schistosoma mansoni and Plasmodium falciparum. Although these 'evolutionary conserved' amino acids account for only 32% of the amino acids in the human hprt protein, they are involved in 76% of the missense mutations at the hprt locus in human T-lymphocytes, 67% in Lesch-Nyhan patients (with severe hprt-deficiency), but only 43% in gout patients (with partial hprt deficiency). This observation supports the notion that evolutionary conserved amino acids constitute functionally important sites in the hprt enzyme, and missense mutations affecting these amino acids will often lead to complete loss of enzyme activity. Substitutions of 'non-conserved' amino acids cause less severe hprt-deficiency (as seen in the gout patients), or may even escape clinical diagnosis. These considerations are important for the understanding of structure-activity relationships in the hprt protein, possible differences between hprt mutational spectra in germ-line and somatic cells, and the mutational spectra induced by specific exogeneous mutagens.

Amino Acid Sequence↗
PubMed2001

Mutations in fibroblast growth factor receptor 2 and fibroblast growth factor receptor 3 genes associated with human gastric and colorectal cancers.

Autosomal dominant disorders of skeletal and cranial development have been linked to fibroblast growth factor receptor (FGFR) 2 and FGFR3. Here we report two identical mutations in FGFR2 that cause craniosynostosis syndromes, Crouzon, Apert, and Pfeiffer in gastric carcinoma. A missense mutation (Ser267Pro) in exon IIIa and a splice site mutation (940-2A-->G) in exon IIIc were detected in gastric cancer patients. Interestingly, these heterozygous somatic mutations are identical to the germinal activating mutations in FGFR2 reported previously in craniosynostosis syndromes. In addition, the two novel mutations of FGFR3 in colorectal carcinomas were identified. All identified mutations occurred at highly conserved sequences, not only in the FGFR family of molecules, but also throughout evolution and clustered in the immunoglobulin-like loop-III domain, highlighting the functional importance of this domain. Our results indicate that FGFR2 and FGFR3, in addition to their potential role in skeletal dysplasias, play an important role in tumorigenesis.

Amino Acid Sequence↗
PubMed1993

Linkage mapping of alpha-2 adrenergic receptor genes to mouse chromosomes 2 and 5.

alpha-2 adrenergic receptors can be subdivided into three related subtypes which are conserved in humans, rats, and mice. In the mouse, these receptors are encoded by three genes (Adra-2a, Adra-2b, Adra-2c). To gain insight into the evolution of this multigene family and to investigate whether these genes are candidates for previously identified mouse mutations, we have determined the map positions of the Adra-2b and Adra-2c genes. The Adra-2a gene has been previously mapped to mouse Chromosome (Chr) 19 (Oakey et al. Genomics 10, 338-344, 1991). Using segregation among recombinant inbred strains of a single-stranded conformational polymorphism specific for alleles of Adra-2b and Adra-2c, we present map positions for these genes on mouse Chrs 2 and 5, respectively. In the case of Adra-2b, these results have been confirmed by an analysis of somatic cell hybrids. In addition, we generate AKXD recombinant inbred strain distribution patterns for 11 previously defined SSLP microsatellite markers, further refining the haplotype maps for these chromosomes. Finally, several candidate mouse mutations that map close to Adra-2b and Adra-2c are discussed.

Animals↗
PubMed2002

[Oocyte apoptosis and evolution of ovarian reserve].

In mammals, the ovarian reserve of primordial follicles is constituted early in fetus, then it becomes progressively exhausted by both follicular development and oocyte apoptosis. At least two third of the oocytes present in the reserve die by apoptosis before birth. Hypotheses of mechanism underlying this process are 1) a "quality control" leading to eliminate meiotic anomalies 2) a deficit in survival factors produced by somatic neighbouring cells 3) a "self sacrifice" or "altruistic death", as previously described in Drosophila. After birth, growth factors and cytokines are main actors of the dialogue which exists between granulosa cells and the oocyte and determines oocyte survival. Mitochondrial factors belonging to bcl-2 family, metabolites of sphingolipids and the aromatic hydrocarbon receptor participate to oocyte apoptosis and can modulate numerical changes in the ovarian reserve. The reserve is quantitatively and qualitatively under both genetic and environmental control. Therapy to preserve ovarian reserve will benefit from better knowledge of molecular and cellular mechanisms regulating oocyte apoptosis. Moreover, recent identification of genes implicated in ovarian premature insufficiency will allow to propose new perspectives to prolong ovarian lifespan.

Animals↗