The Human Plasma Proteome History, Character, and Diagnostic Prospects

Approximately 70 percent of the mutations in cystic fibrosis patients correspond to a specific deletion of three base pairs, which results in the loss of a phenylalanine residue at amino acid position 508 of the putative product of the cystic fibrosis gene. Extended haplotype data based on DNA markers closely linked to the putative disease gene locus suggest that the remainder of the cystic fibrosis mutant gene pool consists of multiple, different mutations. A small set of these latter mutant alleles (about 8 percent) may confer residual pancreatic exocrine function in a subgroup of patients who are pancreatic sufficient. The ability to detect mutations in the cystic fibrosis gene at the DNA level has important implications for genetic diagnosis.

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Identification of the cystic fibrosis gene: genetic analysis.

http://image.sciencenet.cn/olddata/kexue.com.cn/upload/blog/file/2010/11/20101123154018731904.pdf

Presence of fetal DNA in maternal plasma and serum

The aim of this review is to consider the potential benefits that females may gain from mating more than once in a single reproductive cycle. The relationship between non-genetic and genetic benefits is briefly explored. We suggest that multiple mating for purely non-genetic benefits is unlikely as it invariably leads to the possibility of genetic benefits as well. We begin by briefly reviewing the main models for genetic benefits to mate choice, and the supporting evidence that choice can increase offspring performance and the sexual attractiveness of sons. We then explain how multiple mating can elevate offspring fitness by increasing the number of potential sires that compete, when this occurs in conjunction with mechanisms of paternity biasing that function in copula or post-copulation. We begin by identifying cases where females use pre-copulatory cues to identify mates prior to remating. In the simplest case, females remate because they identify a superior mate and 'trade up' genetically. The main evidence for this process comes from extra-pair copulation in birds. Second, we note other cases where pre-copulatory cues may be less reliable and females mate with several males to promote post-copulatory mechanisms that bias paternity. Although a distinction is drawn between sperm competition and cryptic female choice, we point out that the genetic benefits to polyandry in terms of producing more viable or sexually attractive offspring do not depend on the exact mechanism that leads to biased paternity. Post-copulatory mechanisms of paternity biasing may: (1) reduce genetic incompatibility between male and female genetic contributions to offspring; (2) increase offspring viability if there is a positive correlation between traits favoured post-copulation and those that improve performance under natural selection; (3) increase the ability of sons to gain paternity when they mate with polyandrous females. A third possibility is that genetic diversity among offspring is directly favoured. This can be due to bet-hedging (due to mate assessment errors or temporal fluctuations in the environment), beneficial interactions between less related siblings or the opportunity to preferentially fertilise eggs with sperm of a specific genotype drawn from a range of stored sperm depending on prevailing environmental conditions. We use case studies from the social insects to provide some concrete examples of the role of genetic diversity among progeny in elevating fitness. We conclude that post-copulatory mechanisms provide a more reliable way of selecting a genetically compatible mate than pre-copulatory mate choice. Some of the best evidence for cryptic female choice by sperm selection is due to selection of more compatible sperm. Two future areas of research seem likely to be profitable. First, more experimental evidence is needed demonstrating that multiple mating increases offspring fitness via genetic gains. Second, the role of multiple mating in promoting assortative fertilization and increasing reproductive isolation between populations may help us to understand sympatric speciation.

Why do females mate multiply? A review of the genetic benefits.

Summary We have developed a real-time quantitative PCR assay to measure the concentration of fetal DNA in maternal plasma and serum. Our results show that fetal DNA is present in high concentrations in maternal plasma, reaching a mean of 25.4 genome equivalents/ml (range 3.3–69.4) in early pregnancy and 292.2 genome equivalents/ml (range 76.9–769) in late pregnancy. These concentrations correspond to 3.4% (range 0.39%–11.9%) and 6.2% (range 2.33%–11.4%) of the total plasma DNA in early and late pregnancy, respectively. Sequential follow-up study of women who conceived by in vitro fertilization shows that fetal DNA can be detected in maternal serum as early as the 7th wk of gestation and that it then increases in concentration as pregnancy progresses. These data suggest that fetal DNA can be readily detected in maternal plasma and serum and may be a valuable source of material for noninvasive prenatal diagnosis.

/pdf/quantitative-analysis-of-fetal-dna-in-maternal-plasma-and-39ii9hxcbt.pdf

Quantitative Analysis of Fetal DNA in Maternal Plasma and Serum: Implications for Noninvasive Prenatal Diagnosis

Summary and seminatural populations there is a preference for mates with MHC types different from either one’s own Evidence from studies in rodents suggests that mate se- or a foster parent’s strain (Yamazaki et al. 1976, 1978, lection is influenced by major-histocompatibility-com- 1988; Egid and Brown 1989; Potts et al. 1991). Avoidplex haplotypes, with preferences for dissimilar part- ance of mates with similar MHC types would facilitate ners. This study was initiated to determine whether the avoidance of mating with relatives—and the deleteavoidance of a mate with the same HLA haplotype as rious effects of inbreeding that may result. Data on one’s own might be occurring in the Hutterites, a North MHC-based mate choice, from outbred, ethnically hetAmerican reproductive isolate of European ancestry, no- erogeneous human populations, have been inconclusive table for their large sibships, communal lifestyle, and because of the confounding effects of ethnic and racial limited number of five-locus HLA haplotypes (HLA-A, self-preference (Pollack et al. 1982; Rosenberg et al. -B, -C, -DR, and -DQ). HLA haplotypes were known 1983; Jin et al. 1995). The present study was initiated for 411 Hutterite couples. The number of couples ex- to determine whether HLA-based mate choice might be pected to match for a haplotype was calculated in two detectable in an inbred, ethnically homogeneous populaways: first, from population genotype frequencies, with tion with a limited repertoire of HLA genes. account being taken of the nonrandom mating pattern The null hypothesis that HLA genes do not influence with respect to colony lineages, and, second, from com- mate choice was tested in the Hutterites, a Caucasian puter simulations using conservative founder assump- religious isolate living in the northern United States and tions and the exact genealogy of the 411 couples. We western Canada. First we compared the observed numobserved fewer matches for HLA haplotypes between ber of couples matching for an HLA haplotype with an spouses than expected (first method, P A .005; second expected number, by two different methods, as dismethod, P A .020–.067). Among couples who did cussed below. Second, we noted whether the matched match for a haplotype, the matched haplotype was in- haplotypes were equally likely to be inherited from the herited from the mother in 29 cases and from the father mother or the father. Third, we examined the haplotype in 50 cases (P A .018). These results are consistent with composition of the matched haplotypes, hypothesizing the conclusion that Hutterite mate choice is influenced that the frequency of specific haplotypes among the by HLA haplotypes, with an avoidance of spouses with matched haplotypes should reflect the haplotype frehaplotypes that are the same as one’s own. quencies of the sampled population.

https://www.cell.com/ajhg/pdf/S0002-9297(07)64312-2.pdf

HLA and mate choice in humans.

The role that maternal and fetal human leukocyte antigen (HLA) genes play in pregnancy is unknown, but it has been suggested that fetuses whose HLA alleles do not differ from maternal alleles (i.e. histocompatible fetuses) are more likely to be aborted than fetuses with HLA alleles that differ from maternal alleles (i.e. histoincompatible fetuses). To elucidate the role of HLA compatibility in pregnancy, we tested the hypothesis that couples who match for HLA alleles or haplotypes would have reduced fertility because only these couples could produce histocompatible fetuses. We conducted a 10 year prospective study of HLA matching and pregnancy outcome in 111 Hutterite couples, providing information on 251 pregnancies. A logistic regression analysis was performed to determine the effects of HLA matching at HLA regions and loci on pregnancy outcome (fetal loss versus delivery). Significantly increased fetal loss rates were observed among couples matching for the entire 16-locus haplotype (P = 0.002). Among the individual loci, loss rates were increased among couples matching for HLA-B (P = 0.019), HLA-C (P = 0.033) and the complement component, C4 (P = 0.043). We interpret these results as evidence that matching for the entire 16-locus haplotype and/or alleles at an HLA-B-linked locus confers significant risk for fetal loss.

Human leukocyte antigen matching and fetal loss: results of a 10 year prospective study.

Objectives. —To review the rationale for and progress toward the goal of isolating and analyzing fetal cells circulating in maternal blood, and to explore the feasibility of this method in providing noninvasive prenatal cytogenetic diagnosis. Data Sources. —Critical review of data published since the first report (1969) of fetal metaphases in maternal blood. Emphasis is placed on data since the demonstration by polymerase chain reaction (PCR) in 1989 and 1990 that fetal cells indeed exist in maternal blood. Data Synthesis. —Clinical evaluations have not yet been conducted, but it is already clear that molecular technologies have allowed the unequivocal demonstration of fetal cells in maternal blood. Using PCR, our own group and others have demonstrated Y sequences and single gene sequences (eg, hemoglobin LeporeBoston) in maternal blood. Thus, fetal DNA sequences indeed exist in maternal blood. Among the various candidate cells, the most promising appear to be fetal nucleated red blood cells. We isolated nucleated red blood cells on the basis of flow-sorting for the transferrin receptor and glycophorin-A. Enriched samples were then subjected to fluorescence in situ hybridization with chromosome-specific probes. This approach allowed us to detect trisomy 21 and trisomy 18, work later confirmed by others. Conclusions. —Isolating and analyzing fetal cells from maternal blood is clearly possible. Several key biologic questions remain—the optimal cells for isolation, frequency of cells in maternal blood, timing during gestation for maternal blood sampling, and the likelihood of persistence of fetal cells after delivery. Clinical evaluations planned by the National Institute of Child Health and Human Development will determine the sensitivity and specificity of this method and its precise role in prenatal cytogenetic diagnosis. (JAMA. 1993;270:2357-2361)

Isolating Fetal Cells From Maternal Blood: Advances in Prenatal Diagnosis Through Molecular Technology

The American Academy of Pediatrics endorses the US Public Health Service (USPHS) recommendation that all women capable of becoming pregnant consume 400 μg of folic acid daily to prevent neural tube defects (NTDs). Studies have demonstrated that periconceptional folic acid supplementation can prevent 50% or more of NTDs such as spina bifida and anencephaly. For women who have previously had an NTD-affected pregnancy, the Centers for Disease Control and Prevention (CDC) recommends increasing the intake of folic acid to 4000 μg per day beginning at least 1 month before conception and continuing through the first trimester. Implementation of these recommendations is essential for the primary prevention of these serious and disabling birth defects. Because fewer than 1 in 3 women consume the amount of folic acid recommended by the USPHS, the Academy notes that the prevention of NTDs depends on an urgent and effective campaign to close this prevention gap.

Folic acid for the prevention of neural tube defects

Our ability to translate our expanding genetic knowledge into usable information for individual men and women is at best uncertain. Today many adults are offered genetic counseling to help them make reproductive decisions, either before they attempt to achieve a pregnancy or to help them decide whether to continue or terminate one. Taking a family history and, when indicated, recommending certain tests to identify carriers of genetic diseases are standard in obstetrical care. Today's screening tests usually focus on conditions that occur either in the family or in the racial or ethnic group of one or both prospective parents. As . . .

Sherman Elias

Papers

HLA and mate choice in humans.

Human leukocyte antigen matching and fetal loss: results of a 10 year prospective study.

Isolating Fetal Cells From Maternal Blood: Advances in Prenatal Diagnosis Through Molecular Technology

Folic acid for the prevention of neural tube defects

Generic consent for genetic screening.