Family studies show that the Huntington's disease gene is linked to a polymorphic DNA marker that maps to human chromosome 4. The chromosomal localization of the Huntington's disease gene is the first step in using recombinant DNA technology to identify the primary genetic defect in this disorder.

A polymorphic DNA marker genetically linked to Huntington's disease

The hypothesis that red-green "color blindness" is caused by alterations in the genes encoding red and green visual pigments has been tested and shown to be correct. Genomic DNA's from 25 males with various red-green color vision deficiencies were analyzed by Southern blot hybridization with the cloned red and green pigment genes as probes. The observed genotypes appear to result from unequal recombination or gene conversion (or both). Together with chromosome mapping experiments, these data identify each of the cloned human visual pigment genes.

https://science.sciencemag.org/content/sci/232/4747/203.full.pdf

Molecular genetics of inherited variation in human color vision.

Introduction THE pituitary gonadotropins, LH and FSH, play a central role in the mammalian reproductive process. Synthesized in the gonadotropes of the pituitary, the gonadotropins bind to receptors in the gonads leading to effects on steroidogenesis and gametogenesis (Fig. 1). Because these hormones are responsible for sexual maturation and normal reproductive function, the regulation of their synthesis and secretion is essential for the preservation of a species. In recent years, a great deal has been learned about the regulation of synthesis of the gonadotropins using the tools of molecular biology. Before we can fully appreciate these new insights, however, it is important to understand the complex structure of the gonadotropins and to summarize what is known about the regulation of their secretion. In this review, we will discuss the structure of the gonadotropin subunits, the structure of the genes that encode them, and the regulation of their secretion and synthesis.

Molecular biology of the pituitary gonadotropins.

A search for POU domain sequences expressed in the human retina has led to the identification of three closely related genes: Brn-3a, Brn-3b, and Brn-3c. The structure and expression pattern of Brn-3b was reported earlier (Xiang et al., 1993); we report here the structures and expression patterns of Brn-3a and Brn-3c. Antibodies specific for each Brn-3 protein were generated and shown to label only ganglion cells in a variety of vertebrate retinas. A complex pattern of strongly and weakly immunolabeled ganglion cells was observed in mouse, cat, and monkey retinae. In mouse and cat retinae, Brn-3a and Brn-3b proteins are found in a large fraction of ganglion cells, whereas Brn-3c is present in fewer ganglion cells. In the cat retina, anti-Brn-3a immunoreactivity was strong in the small ganglion cells (gamma cells) and weak in the remaining ganglion cells (alpha and beta cells); anti- Brn-3b immunoreactivity was present in all ganglion cells; and anti- Brn3c immunoreactivity was confined to the small ganglion cells. Immunolabeling of macaque retinae following retrograde labeling from the lateral geniculate nucleus revealed strong anti-Brn-3a immunoreactivity in a minority of retrogradely labeled P-type ganglion cells, and weak Brn-3a immunoreactivity in all of the remaining P- and M-type ganglion cells. In the same retinae, strong anti-Brn-3b immunoreactivity was seen in nearly all P-type ganglion cells and weak immunoreactivity in nearly all M-type ganglion cells. Each of the Brn-3- specific antibodies also labeled subsets of neurons in the dorsal root and trigeminal ganglia, suggesting that primary somatosensory neurons and retinal ganglion cells share genetic regulatory hierarchies. In vitro selection of an optimal DNA binding site using the Brn-3b POU domain has revealed a consensus [(A/G)CTCATTAA(T/C)] that is recognized by each of the Brn-3 POU domains and is distinct from binding sites previously described for other POU domain proteins.

The Brn-3 family of POU-domain factors: Primary structure, binding specificity, and expression in subsets of retinal ganglion cells and somatosensory neurons

https://www.cell.com/cell/pdf/0092-8674(91)90285-7.pdf

B cell lymphoma-associated chromosomal translocation involves candidate oncogene lyt-10, homologous to NF-κB p50

It is estimated that the human haploid genome is composed of 3 × 109 nucleotides and that only 10% of it consists of coding and regulatory sequences.14 If a gene is approximately 104 nucleotides in length, which includes the coding region and the intervening and flanking sequences, this estimate would predict that there are about 3–10 × 104 human genes coding for different protein products. Since gene clustering in humans has become evident (for example, the hemoglobin, immunoglobin, and HLA clusters), these estimated gene products may be grouped in from 3000 to 15,000 clusters.15 Further, based upon genetic and molecular studies of microorganisms, Drosophila, and the mouse, there are perhaps 5 × 104 structural genes estimated in humans,14,106,183 which is in agreement with the number of estimated protein products in the human genome. Mapping the human genome involves partitioning the total number of genes into individual maps representing the 24 different human nuclear chromosomes and linearly ordering them on each chromosome. A similar exercise has mapped the 37 genes encoded in the DNA of the mitochondrial genome.2

Mapping the Human Genome, Cloned Genes, DNA Polymorphisms, and Inherited Disease

The chromosomal locations of the genes for the common alpha subunit of the glycoprotein hormones and the beta subunit of chorionic gonadotropin in humans and mice have been determined by restriction enzyme analysis of DNA isolated from somatic cell hybrids. The CG alpha gene (CGA), detected as a 15-kb BamHI fragment in human DNA by hybridization to CG alpha cDNA, segregated with the chromosome 6 enzyme markers ME1 (malic enzyme, soluble) and SOD2 (superoxide dismutase, mitchondrial) and an intact chromosome 6 in human-rodent hybrids. Cell hybrids containing portions of chromosome 6 allowed the localization of CGA to the q12 leads to q21 region. The greater than 30- and 6.5-kb BamHI CGB fragments hybridizing to human CG beta cDNA segregated concordantly with the human chromosome 19 marker enzymes PEPD (peptidase D) and GPI (glucose phosphate isomerase) and a normal chromosome 19 in karyotyped hybrids. A KpnI-HindIII digest of cell hybrid DNAs indicated that the multiple copies of the CG beta gene are all located on human chromosome 19. In the mouse, the alpha subunit gene, detected by a mouse thyrotropin (TSH) alpha subunit probe, and the CG beta-like sequences (CG beta-LH beta), detected by the human CG beta cDNA probe, are on chromosomes 4 and 7, respectively.

Chromosome assignment of genes encoding the alpha and beta subunits of glycoprotein hormones in man and mouse.

The human gene for parathyroid hormone (PTH) was chromosomally mapped using human-rodent hybrids and Southern filter hybridization of cell hybrid DNA. A recombinant DNA probe containing human PTHcDNA insert (pPTHm122) hybridized to a 3.7-kb fragment in human DNA cleaved with the restriction enzyme EcoRI. By correlating the presence of this fragment in somatic cell hybrid DNA with the human chromosomal content of the hybrid cells, the PTHgene was mapped to the short arm of the chromosome 11.

Human parathyroid hormone gene (PTH) is on short arm of chromosome 11.

At least ten leukocyte interferon genes and the single known fibroblast interferon gene have been localized on the pter leads to q12 region of human chromosome 9. Gene mapping was accomplished by blot hybridization of cloned interferon complementary DNA to DNA from human-mouse cell hybrids with a translocation involving human chromosome 9. Supporting evidence suggests these genes are clustered.

https://science.sciencemag.org/content/sci/218/4570/373.full.pdf

Clustering of leukocyte and fibroblast interferon genes of human chromosome 9.

Ul small nuclear RNA (Ul snRNA) is encoded by a large family of genes (30–125 copies/haploid genome) which are transcribed by RNA polymerase II. Ul snRNA is thought to function in gene splicing. Since the Ul genes were found to be >20 kb apart by analyzing genomic phage clones, the chromosomal location of Ul genes in the human genome was determined using Southern filter analysis of DNA isolated from human-rodent somatic cell hybrids and by in situ hybridization. Human DNA digested with PvuII and probed with a Ul-specific probe, pD2, show several major hybridizing fragments. Of these, two human PvuII fragments of 1.4 kb and 2.4 kb had unique mobilities compared to mouse fragments. In a study of 19 cell hybrids, the human-specific Ul fragments segregated with the chromosome 1 markers peptidase C and adenylate kinase 2. All other chromosomes showed>-19% discordancy. An additional 13 karyotyped cell hybrids, analyzed by Southern filter analysis, confirmed the assignment of this class of Ul genes to chromosome 1. Additional digests with MspI and PstI indicated that most Ul genes are located on chromosome 1. To determine if the Ul RNAs are located predominantly at one site or dispersed over chromosome 1, a tritium-labeled Ul probe was hybridized in situ to metaphase chromosomes. The majority of the grains were at band 1p36.3, suggesting that most of the Ul genes are located in this region.

Susan L. Naylor

Papers

Mapping the Human Genome, Cloned Genes, DNA Polymorphisms, and Inherited Disease

Chromosome assignment of genes encoding the alpha and beta subunits of glycoprotein hormones in man and mouse.

Human parathyroid hormone gene (PTH) is on short arm of chromosome 11.

Clustering of leukocyte and fibroblast interferon genes of human chromosome 9.

Localization of Human U1 Small Nuclear RNA Genes to Band p36.3 of Chromosome 1 by In Situ Hybridization