Inbreeding and the genetic complexity of human hypertension

Considerable uncertainty exists regarding the genetic architecture underlying common late-onset human diseases. In particular, the contribution of deleterious recessive alleles has been predicted to be greater for late-onset than for early-onset traits. We have investigated the contribution of recessive alleles to human hypertension by examining the effects of inbreeding on blood pressure (BP) as a quantitative trait in 2760 adult individuals from 25 villages within Croatian island isolates. We found a strong linear relationship between the inbreeding coefficient (F) and both systolic and diastolic BP, indicating that recessive or partially recessive quantitative trait locus (QTL) alleles account for 10-15% of the total variation in BP in this population. An increase in F of 0.01 corresponded to an increase of approximately 3 mm Hg in systolic and 2 mm Hg in diastolic BP. Regression of F on BP indicated that at least several hundred (300-600) recessive QTL contribute to BP variability. A model of the distribution of locus effects suggests that the 8-16 QTL of largest effect together account for a maximum of 25% of the dominance variation, while the remaining 75% of the variation is mediated by QTL of very small effect, unlikely to be detectable using current technologies and sample sizes. We infer that recent inbreeding accounts for 36% of all hypertension in this population. The global impact of inbreeding on hypertension may be substantial since, although inbreeding is declining in Western societies, an estimated 1 billion people globally show rates of consanguineous marriages >20%.     

On the complexity measures of genetic sequences

MOTIVATION: It is well known that the regulatory regions of genomes are highly repetitive. They are rich in direct, symmetric and complemented repeats, and there is no doubt about the functional significance of these repeats. Among known measures of complexity, the Ziv-Lempel complexity measure reflects most adequately repeats occurring in the text. But this measure does not take into account isomorphic repeats. By isomorphic repeats we mean fragments that are identical (or symmetric) modulo some permutation of the alphabet letters. RESULTS: In this paper, two complexity measures of symbolic sequences are proposed that generalize the Ziv-Lempel complexity measure by taking into account any isomorphic repeats in the text (rather than just direct repeats as in Ziv-Lempel). The first of them, the complexity vector, is designed for small alphabets such as the alphabet of nucleotides. The second is based on a search for the longest isomorphic fragment in the history of sequence synthesis and can be used for alphabets of arbitrary cardinality. These measures have been used for recognition of structural regularities in DNA sequences. Some interesting structures related to the regulatory region of the human growth hormone are reported.     

Quantifying and analyzing the network basis of genetic complexity

Genotype-to-phenotype maps exhibit complexity. This genetic complexity is mentioned frequently in the literature, but a consistent and quantitative definition is lacking. Here, we derive such a definition and investigate its consequences for model genetic systems. The definition equates genetic complexity with a surplus of genotypic diversity over phenotypic diversity. Applying this definition to ensembles of Boolean network models, we found that the in-degree distribution and the number of periodic attractors produced determine the relative complexity of different topology classes. We found evidence that networks that are difficult to control, or that exhibit a hierarchical structure, are genetically complex. We analyzed the complexity of the cell cycle network of Sacchoromyces cerevisiae and pinpointed genes and interactions that are most important for its high genetic complexity. The rigorous definition of genetic complexity is a tool for unraveling the structure and properties of genotype-to-phenotype maps by enabling the quantitative comparison of the relative complexities of different genetic systems. The definition also allows the identification of specific network elements and subnetworks that have the greatest effects on genetic complexity. Moreover, it suggests ways to engineer biological systems with desired genetic properties.     

Cnidarians and ancestral genetic complexity in the animal kingdom

Eleven of the twelve recognized wingless (Wnt) subfamilies are represented in the sea anemone Nematostella vectensis, indicating that this developmentally important gene family was already fully diversified in the common ancestor of 'higher' animals. In deuterostomes, although duplications have occurred, no novel subfamilies of Wnts have evolved. By contrast, the protostomes Drosophila and Caenorhabditis have lost half of the ancestral Wnts. This pattern -- loss of genes from an ancestrally complex state -- might be more important in animal evolution than previously recognized.     

Ancestral genetic complexity of arachidonic acid metabolism in Metazoa

Eicosanoids play an important role in inducing complex and crucial physiological processes in animals. Eicosanoid biosynthesis in animals is widely reported; however, eicosanoid production in invertebrate tissue is remarkably different to vertebrates and in certain respects remains elusive. We, for the first time, compared the orthologs involved in arachidonic acid (AA) metabolism in 14 species of invertebrates and 3 species of vertebrates. Based on parsimony, a complex AA-metabolic system may have existed in the common ancestor of the Metazoa, and then expanded and diversified through invertebrate lineages. A primary vertebrate-like AA-metabolic system via cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP) pathways was further identified in the basal chordate, amphioxus. The expression profiling of AA-metabolic enzymes and lipidomic analysis of eicosanoid production in the tissues of amphioxus supported our supposition. Thus, we proposed that the ancestral complexity of AA-metabolic network diversified with the different lineages of invertebrates, adapting with the diversity of body plans and ecological opportunity, and arriving at the vertebrate-like pattern in the basal chordate, amphioxus.     

The complexity of genetic variation in a simple immune system

Fruitflies derived from a wild population vary in their resistance to infection with the bacterial pathogen Serratia marcescens. A survey of nucleotide diversity in 21 genes involved in innate immunity concluded that 16 genes had polymorphisms associated with resistance to this specific pathogen. However, the effects of individual polymorphisms on the resistance phenotype were modest, and epistatic interactions appeared to be common. What might these findings tell us about genetic resistance to infection in humans?     

Radiosensitivity of murine T-lymphocyte cytotoxicity

A biphasic curve was observed when surviving allogeneic lytic activity was plotted as a function of irradiation delivered before sensitization. Flow cytometry analysis demonstrated that the number of cells was reduced in response to increasing dose and that subset precursors Lyt 1+2+ were proportionally more radiosensitive than the other subsets. Paradoxically, the presence of exogenous T-cell growth factor (TCGF) in limiting dilution analysis changed the shape of the survival curve, and the mere addition of TCGF or Lyt 2- TCGF-producing cells abrogated the irradiation effect even though they were not shown to be the target of low dose irradiation in flow cytometry analysis. It is proposed that TCGF acted by enhancing the proliferation of surviving cells. This effect may be responsible for the relative radioresistance at higher doses due to enhanced availability of TCGF for the remaining cells.     

Repair-induced Changes in Yeast Radiosensitivity

Potentially lethal X-ray or ultraviolet damage in the diploid yeast, Saccharomyces cerevisiae, can be reversed if the irradiated cells are incubated in distilled water or buffer for a number of hours prior to plating. This phenomenon is called liquid-holding recovery. We found that the liquid-holding procedure served not only to restore the viability of the irradiated cells, but also to alter their sensitivity to further doses of radiation. Specifically, the ultraviolet sensitivity of cells which had undergone liquid-holding recovery was markedly decreased, whereas their X-ray sensitivity appeared to be slightly increased. These sensitivity changes were qualitatively the same irrespective of whether the initial radiation exposure was to X rays or ultraviolet light. (In contrast, the radiation sensitivity of cells which had undergone maximal photoreactivation was essentially the same as that of untreated controls.) It is suggested that these changes in radiosensitivity are the result of structural alterations induced in the cell's deoxyribonucleic acid by the execution of at least the initial steps of a deoxyribonucleic acid repair process during the liquid-holding period.