Concerning the pancreatic function, a Canadian study showed that the patients with one or two missense mutations R117H, R334W, R347P, A455E or P574H have a conserved exocrine pancreatic function (PS or pancreatic sufficiency), as compared to those having two alleles of splicing mutations, nonsense or frame shift mutations and some mutations of missense which always lead to pancreatic insufficiency (PI or pancreatic insufficiency) (Kristidis 1992). The mutations associated with a normal pancreatic function are considered as moderate and those associated with pancreatic insufficiency as severe. Similarly, the patients having a PI mutation on one allele and a PS mutation on the other have a phenotype PS. With a PS mutation, the activity of the CFTR protein is sufficient for the pancreatic function. However, multi centric study showed that out of 396 homozygotes DF508, 10 conserve a pancreatic function (Consortium, 1993).
This type of analysis is complicated by several phenomena. The effect of one mutation can be modified by a second mutation inherited in cis on the same allele. Two cases have been described; the polymorphism of the polypyrimidic tract of the intron 8, and the association of two nucleotide substitution on the same allele.
The group of Tümmler at Hanover described a patient carrying a complex genotype R553X / DF508-R553Q (Dork 1991). The patient presents a pancreatic sufficiency associated with a typical pulmonary involvement but an abnormally low sweat test compared to 9 patients R553X / DF508, suggesting that the mutation R553Q can modify the effect of DF508. This hypothesis was partly valid in vitro (Teem 1993). This same group also described two unrelated patients carrying this genotype: DF508 / S1251N-F508C. They proposed that the polymorphism F508C could aggravate the effect of S1251N (Kalin 1992).
A European collaborative study (EWGCFG 1990) comprising of 4871 CF chromosomes and 3539 normal chromosomes showed the great heterogeneity of this anomaly. There is a north-west/south-east gradient, for example 88% of DF508 cases found in Denmark and 50% in Italy. In the French population, the principal mutation (DF508) represents approximately 65-70% of CF chromosomes, with strong regional variations being 64% in Languedoc-Roussillon to 81% in occidental Britannia. This elevated frequency suggests the possible existence of a selective advantage of heterozygotes in the north-European populations. The analysis of genetic markers associated with DF508 suggests that only one mutational event has occurred in the past (Morral 1994). To explain the spread of this mutation in European population, the hypothesis of a selective advantage of heterozygotes was proposed. For example, the heterozygotes would be protected against dehydration due to diarrhea caused by enterotoxins of Escherichia coli and of Vibrio cholerae (Baxter 1988). The species have in common the production of toxins that increase the concentration of cAMP or of cGMP in the enterocytes and thus increase the secretion of chloride. If we consider that the heterozygotes have 50% the activity of CFTR, their secretion in response to bacterial toxins would be less marked than in the homozygotes and so there would be less dehydration improving their survival. Pier et al. recently suggested that the first extracellular loop of CFTR is necessary for the internalization of S. typhi in the intestinal epithelial cells (Pier et al., 1998). The DF508 protein, associated with a decreased expression of CFTR to the epithelial surfaces, decrease the entry of pathogen into the intestinal epithelium thus providing a protection against this infection.
Familiar examples ofprotozoa are flagellates (incl.
One of the four listed hypotheses is, "Life is coeternal with matter and has no beginning; life arrived on the Earth at the time of the origin of the earth or shortly thereafter."
, December 23: Lord Kelvin's address to British scientists, in 1871.
The early description of cystic fibrosis (CF) dates back to late 30s
Mutations which improve the efficiency of recombination should affect either the proteins which mediate recombination, or their substrate, DNA itself. The former mutations would be localized, the latter dispersed. Studies of hybridization between RNA molecules have suggested that recombination may be initiated by the 'kissing' of the tips of stem-loops [Tomizawa, 1984. Cell , 861]. This predicts that, in the absence of other constraints, mutations assisting formation of stem-loops would be favoured. By comparing the folding of normal and shuffled DNA sequences [Le & Maizel, 1989. J Theor Biol , 495], I give evidence for an evolutionary selective pressure to distribute stem-loop-forming potential generally throughout eukaryotic genomes. I propose that this early pressure came into conflict with later local pressures to impose information on specific function. The conflict was accommodated by permitting DNA concerned with specific function to evolve in dispersed segments. Traces of this conflict are seen in some modern genes.
Developmental dyslexia - ScienceDirect
Example of a Go-plot is (from , these authors describe an significant excess of introns in the linker regions defined through he overlap in the Go-plot).
SIDS and Other Sleep-Related Infant Deaths ..
For example, Manfred Eigen of Germany's Max Planck Institute says, "There is no doubt that proteins, which are more easily formed, were first on the scene" .