Barton Childs

The human disease network

A network of disorders and disease genes linked by known disorder–gene associations offers a platform to explore in a single graph-theoretic framework all known phenotype and disease gene associations, indicating the common genetic origin of many diseases. Genes associated with similar disorders show both higher likelihood of physical interactions between their products and higher expression profiling similarity for their transcripts, supporting the existence of distinct disease-specific functional modules. We find that essential human genes are likely to encode hub proteins and are expressed widely in most tissues. This suggests that disease genes also would play a central role in the human interactome. In contrast, we find that the vast majority of disease genes are nonessential and show no tendency to encode hub proteins, and their expression pattern indicates that they are localized in the functional periphery of the network. A selection-based model explains the observed difference between essential and disease genes and also suggests that diseases caused by somatic mutations should not be peripheral, a prediction we confirm for cancer genes.

Human disease genes.

The complete human genome sequence will facilitate the identification of all genes that contribute to disease. We propose that the functional classification of disease genes and their products will reveal general principles of human disease. We have determined functional categories for nearly 1,000 documented disease genes, and found striking correlations between the function of the gene product and features of disease, such as age of onset and mode of inheritance. As knowledge of disease genes grows, including those contributing to complex traits, more sophisticated analyses will be possible; their results will yield a deeper understanding of disease and an enhanced integration of medicine with biology.

The genetics of specific reading disability.

Members of the immediate families of twenty children with specific reading disability were examined to determine the prevalence of reading disability within the families. A procedure was developed for identifying adults who may have compensated for a disability manifested more clearly in childhood. Forty-five percent of 75 first-degree relatives of the parents were affected and there was a significantly greater number of affected male relatives than females. No single mode of genetic transmission is evident after inspection of the pedigrees. It is suggested that the disorder is genetically heterogeneous and that subgroups of disabled readers should be looked for.

X-Linked Hypoxanthine-Guanine Phosphoribosyl Transferase Deficiency: Heterozygote Has Two Clonal Populations

Clones of skin fibroblasts cultured from the mother of two sons with X-linked hypoxanthine-guanine phosphoribosyl transferase deficiency (Lesch-Nyhan syndrome) were assayed for activity of this enzyme by measurement of the incorporation of 3H-guanine into guanylic acid as counts per minute per microgram of protein and by autoradiography. The demonstration of two populations of clones, wild-type clones with normal enzyme activity and mutant clones unable to incorporate 3H-guanine, is evidence that the locus for hypoxanthineguanine phosphoribosyl transferase on one of the X chromosomes is inactive.

Age at onset and causes of disease.

We know a good deal about the origins and pathogenesis of monogenic diseases, but we still know too little of how and what the genes contribute to multifactorial diseases. We seldom know which loci are involved, or which alleles inhabit them. Nor can we say how the effects of each gene modify those of others in the deranged homeostasis that constitutes the phenotype. And we can seldom specify the elements of the environment that interact with the effects of the genes.

Preliminary evidence for genetic anticipation in Crohn's disease

BACKGROUND The term genetic anticipation is used to describe earlier onset of disease, increased severity, or both, in succeeding generations of families affected by a particular disease. This process has been linked with expanded genomic trinucleotide repeat regions in some neurological disorders. Crohns disease, an inflammatory bowel disorder, has genetic influences, which remain undefined. We studied pairs of two-generation first-degree relatives with Crohns disease to seek evidence for genetic anticipation in this disorder. METHODS Through retrospective review of the records of 552 patients treated for Crohns disease at Johns Hopkins Hospital, we identified 27 pairs of two-generation first-degree relatives. We also studied 32 such pairs identified through a multicentre survey. After exploratory analyses by t tests, a generalised estimating equations approach was used to fit a marginal regression model. FINDINGS The age at diagnosis was earlier in the younger member of the pair both in the Johns Hopkins Hospital dataset (18.9 [SE 6.9] vs 31.4 [12.0] years) and in the multicentre survey dataset (16.9 [7.4] vs 33.1 [11.9] years). The regression model confirmed the findings: the best-fitting model for the Johns Hopkins Hospital data showed an average 10.8 (SE 4.2) year difference in age at diagnosis between parent and child; that for the multicentre data showed an average difference of 15.1 (1.5) years. There was evidence of a further difference between the second and third generations. Disease was more extensive in the offspring than in the parent for 15 of the 27 pairs at Johns Hopkins Hospital; in 13 of these pairs the affected parent was the father. INTERPRETATION The evidence of a lower age at diagnosis and a greater extent of disease in the younger member of two-generation pairs affected by Crohns disease, as well as the association with paternal transmission, suggest that genetic anticipation does occur in Crohns disease. A search for triplet repeat regions is warranted.

Glucose-6-Phosphate Dehydrogenase in Drosophila: X-Linked Electrophoretic Variants

Three electrophoretic patterns of glucose-6-phosphate dehydrogenase have been found in wild-type strains of Drosophila melanogaster. Genetical control of the variants in enzyme mobility (fast or slow) is X-linked; strains possessing both bands (fast and slow) appear to be heterogeneous, having individuals of three types (fast, slow, and double).

Genetic Susceptibility of Benign Prostatic Hyperplasia

In an effort to provide new insight into the etiology of benign prostatic hyperplasia (BPH), an evaluation of genetic factors was performed. Recognizing that early age of onset is a marker for hereditary disease, we performed a case-control study of men with early onset of significant BPH. Men in the youngest quartile (less than 64 years old) with a large prostate (greater than 37 gm. resected tissue) who underwent surgery for BPH were identified as case probands from 909 consecutive prostatectomies for BPH. Control probands, selected because of the ability to distinguish treatment for benign prostate disease from treatment for malignant prostate disease, were women whose spouses underwent radical prostatectomy during the same interval. Male relatives of men with early onset of BPH had a 66% cumulative lifetime risk of prostatectomy for BPH, compared to a 17% cumulative risk among control relatives (p = 0.001). A 4-fold increase in age-specific risk of prostatectomy for BPH was present among relatives of men who had undergone prostatectomy for BPH (p = 0.0003), while brothers of these affected cases had a 6-fold increase in risk (p = 0.0089) compared to controls. To determine the likelihood that genetic factors account for this familial aggregation of BPH, segregation analysis was done. Although the small sample size prevented rigorous exclusion of nongenetic models, direct comparison of mendelian and nongenetic models showed that mendelian transmission provided the best overall explanation of the observed familial aggregation. The optimal model suggested mendelian dominant inheritance of a gene associated with early age at onset of BPH. These findings identify family history of BPH as a risk factor for clinical BPH and suggest the presence of a predisposing gene in patients with early onset BPH. Evidence of dominant mendelian transmission of this allele provides a framework for genetic studies to characterize this gene and elucidate the development of BPH in general.

X-Linked 6-Phosphogluconate Dehydrogenase in Drosophila: Subunit Associations

6-Phosphogluconate dehydrogenase (PGD) subunits have been dissociated and reassociated in vitro. The intermediate PGD of the heterozygous phenotype is reproduced by reassociation in vitro of subunits derived from the two types of PGD from homozygous flies. This result has a bearingon gene action in the diploid organism and on the mechanism of dosage compensation in Drosophila melanogaster.

A Follow-Up Study of Dyslexic Boys.

Over 500 men who attended the Gow School, an independent school for boys with developmental dyslexia, were given a follow-up questionnaire from 1 to 38 years after they left the school. More than half had graduated from college; business was the most frequently chosen major in college; most were employed in managerial or related business positions; and their adult reading habits and attitudes did not compare well with those of other men of similar socioeconomic backgrounds. Socioeconomic status and IQ were not predictive of adult outcome among these men in contrast to their effect in the general population. An important result was that severity of the reading problem upon entrance to Gow and the academic and remedial progress of the men while at the school were highly predictive of adult educational, occupational, and attitudinal status.