More Genetics 2010 abstracts

These selections mostly related to sex differences:

The dynamics of the human sex ratio from conception to birth. Steven Orzack. Fresh Pond Research Institute, Cambridge, MA.
We describe the demographic trajectory of the human sex ratio from conception to birth by analyzing data derived from 1) three-to-five day old embryos, 2) induced abortions, 3) fetuses that have undergone chorionic-villus sampling or amniocentesis, and 4) US census records of fetal mortality and live births. The estimated sex ratio just after conception is 0.5 (proportion male), which contradicts the common belief that the sex ratio at conception is male-biased. The sex ratio among normal embryos (those lacking any major chromosomal abnormalities such as aneuploidy) is significantly female-biased. Thereafter, the estimated sex ratio increases and becomes male-biased after approximately 8 -12 weeks of gestation. It levels off after approximately 20 weeks and then starts to decline slowly after 28 weeks until 37 weeks, when it declines markedly and becomes female-biased. The form of this trajectory suggests that there is an early relative excess of female mortality followed by a later relative excess of male mortality, with net female mortality during pregnancy exceeding male mortality; this is an important insight into the early development of human beings.

Mechanisms underlying sexual differentiation of the brain and behavior. Nirao M Shah. Anatomy, University of California, San Francisco, San Francisco, CA.
Sexually reproducing species often exhibit gender dimorphisms in behaviors such as courtship, aggression, and parental care. In vertebrates, steroid hormones produced by the testes and ovaries exert a profound influence on the development and activation of neural circuits that control sex specific behaviors. Both testosterone and estrogen are essential for male typical behaviors in many vertebates. How these two signaling pathways interact to control masculinization of the brain and behavior remains poorly understood. We have used genetic strategies to address this long standing question, using the mouse as a model organism. We will present evidence demonstrating that estrogen represents a molecular switch that controls the masculine repertoire of mating, aggression, and territorial marking behavior. By contrast, testosterone signaling via its cognate receptor, the androgen receptor (AR), serves as a gain control mechanism to amplify the display of such male behaviors. We will also present evidence demonstrating that estrogen acts via a positive feedback loop to control masculinization of specific neuronal populations, and that estrogen is necessary and sufficient to control the sexual differentiation of AR in neurons. These and other results indicate that estrogen is genetically upstream of testosterone signaling for masculinizing the brain and behavior. Gonadal hormones appear to be one set of master regulators for the control of sexually dimorphic behaviors. These steroids must, in turn, modulate the expression of target genes via their nuclear receptors such that these targets control specific physiological and behavioral modules. We will present results that are in striking agreement with this notion: we have uncovered genes whose expression appears to be regulated by gonadal steroids, and whose function is essential for the display of some, but not all, dimorphic behaviors. Thus, our studies have begun to uncover some of the molecular logic underlying sexual differentiation of the brain and behavior in mammals.

Pink or Blue? Genetic Influence on Sex Differences in the Brain. Eric Vilain. UCLA Department of Human Genetics and Center for Gender-Based Biology, Los Angeles, CA.
Male and female brains are anatomically and biochemically different, and sex differences influence a large array of human traits and disorders. The traditional view that all meaningful sex differences in the brain are exclusively influenced by gonadal secretions has been recently challenged. The accumulated evidence from animal and human models provides strong arguments for a role - whether isolated or in concert with gonadal hormones - of sex chromosomes and of sex-specific genes. We will show examples of the role of genes expressed in a sex-specific fashion (such as the maledetermining transcription factor Sry) on a variety of phenotypes. Behavioral traits such as sexual orientation and gender identity are also highly sexually dimorphic. We will present the biological approaches that have been used to determine the role of genetics and environment in the development of these complex traits.

Sexual differentiation of human brain and behavior. Melissa Hines. Univ of Cambridge, Cambridge, UK.
Sexual differentiation begins at conception, when genetic information starts the processes that lead to masculine or feminine development. One of these processes is development of the gonads as testes or ovaries. Gonadal hormones, particularly testosterone, then play a major role in sex-typical development, not just of the external genitalia, but also of the brain and behavior. In humans, the influences of testosterone begin at about week 7 of gestation, when the male testes become active. The ovaries are relatively quiescent, and the main hormonal difference between male and female fetuses appears to be in testicular hormones. Testicular hormones masculinize the genitalia, and influence neurobehavioral development. Neurobehavioral influences of testosterone have been documented extensively in non-human mammals. These studies show that testosterone, and hormones produced from it, influence basic neurodevelopmental processes, such as cell survival, neuronal growth and neurochemical specification, as well as behavior. The strongest evidence that testosterone influences human behavioral development comes from studies of children’s sex-typical play. Girls exposed to high levels of testosterone prenatally, because of the genetic disorder, congenital adrenal hyperplasia, show masculinized toy and activity preferences, including increased preferences for male playmates, and for toys like cars and trucks, and reduced preferences for toys like dolls and tea sets. Girls whose mothers took androgenic hormones during pregnancy show similar masculinized behavior to that of girls with CAH, whereas children whose mothers took anti-androgens during pregnancy show reduced male-typical play. Normal variability in testosterone, measured in maternal blood or in amniotic fluid during gestation, also relates to sex-typical play. Sexual orientation, gender identity, aggression and empathy also are influenced by the prenatal hormone environment, although the strength of the hormone-behavior relationship differs from one outcome to another. Overall, findings suggest that prenatal exposure to testosterone is one of the many factors that influence the development of human sextyped behavior.

Gene expression profile of peripheral WBC differs among ethnic groups with type 2 diabetes. Jinghe Mao1, Junmei Ai2, Marketta Blue1, Ming Shenwu1, Adrienne Wells1, Youping Deng3. 1) Dept Biol, Tougaloo Col, Tougaloo, MS; 2) Dept Computer Sci, Uni Southern Mississippi, Hattiesburg, MS; 3) SpecPro Inc, Vicksburg, MS.
Type 2 diabetes and its complications are tremendous sources of mortality, morbidity, and cost in the U.S. African-Americans have higher risks for developing type 2 diabetes than Caucasians. The purpose of this work is to compare the gene expression profiles of Caucasians and African- Americans with type 2 diabetes and to understand the underlying mechanisms. To accomplish this objective an oligo DNA microarray of peripheral white blood cells (WBC) was performed. We obtained a total of 144 samples from 72 Caucasians (32 healthy and 40 diabetic subjects) and 72 African-Americans (28 healthy and 44 diabetic subjects) from Mississippi. Microarray analysis showed that a total of 28 genes were found to be differentially expressed between diabetic and control groups (a fold change of <1.4 or >1.4 with a P value <0.05). These genes were mainly found in three functional categories: immune response (10 genes down-regulated; 2 genes up-regulated), lipid metabolism (5 genes down-regulated; 1 gene up-regulated) and organismal injury and abnormalities (7 genes down-regulated; 1 gene up-regulated). Of the 28 genes, 5 were known type II diabetes related genes. These changes were validated using quantitative RT-PCR. Transcriptome analysis also showed that 574 genes were up/downregulated in African-American diabetic patients whereas 200 genes were up/down-regulated in Caucasian patients when compared to respective racial normal subjects. Pathway study revealed that inositol metabolism and Wnt/â-Catenin pathways are significantly up-regulated in African- American diabetic patients. Our results indicate that genes are differentially expressed between African American and Caucasian with type 2 diabetes and peripheral WBC can be potentially used to identify novel biomarkers for diagnosis of type 2 diabetes.

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