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Human-Mouse Comparisons Identify Candidate Sequences

A more detailed version of this article appeared in Science on July 6, 2001.

Less than 5% of the 3.2 billion bases in the human genome sequence is thought to be occupied by genes, regulatory elements controlling gene expression, and other DNA regions that serve important known biological functions. One of the most efficient ways to identify these rare sequence features is to compare human DNA sequence with that of a related but divergent species such as the mouse. The power of the mouse model in studying human disease and in dissecting gene function adds an important dimension to such comparisons.

A clone-based physical map assembled by scientists at Lawrence Livermore National Laboratory (LLNL) provided the framework for completing the draft sequence of human chromosome 19 (HSA19) nearly a year ago. Since then a DOE Joint Genome Institute (JGI) team headed by Lisa Stubbs at LLNL has focused on functionally annotating this chromosome, beginning with an effort to identify and delineate all functional components of resident genes.

Spanning some 65 to 70 million bases and containing an estimated 1100 genes, HSA19 is one of the smallest, yet most gene-dense, of the 24 human chromosomes. To provide a tool for functional annotation and evolutionary studies, the JGI-LLNL group isolated and sequenced sets of overlapping BAC clones spanning mouse DNA sequences related to HSA19. The draft sequence's high quality and solid anchorage between human sequence and related mouse clones enabled an unusually comprehensive view of the conserved (common to both mouse and human) and nonconserved features distributed across the chromosome.

Comparison of related mouse and HSA19 DNA identified more than 12,000 conserved sequence elements, including candidate undiscovered human exons (protein-coding gene fragments) as well as whole novel genes and an estimated 4000 candidate regulatory DNA sequences. Analyses showed that highly conserved versions of virtually all single-copy human genes are found in mouse DNA and that mouse and human genes are organized in very similar ways.

However, Stubbs and her team also noted striking species-specific differences in the content and functional capacity of certain types of genes, including those encoding zinc-finger transcription factors, olfactory receptors, pheromone receptors, cytochrome P450, serine proteases, and many other types of proteins. These types of genes, which often are found organized into tandem clusters of 5 to more than 60, are present in different numbers and types in mouse and human DNA. This reflects the very active duplication, divergence, and either functional or total loss of genes since separation of rodent and primate lineages. Stubbs and her colleagues estimate that these changes have given rise to at least 100 actively expressed genes that are unique to either humans or mice. These lineage-specific genes are likely to have significant impacts on biology, defining at least some of the major physiological, morphological, and behavioral differences between rodents and primate species. HSA19 is related to mouse DNA found in 15 conserved segments from different portions of mouse chromosomes 7, 8, 9, 10, and 17. Because both human and mouse sequences were derived from precisely mapped clones, the JGI team could identify the boundaries or "breakpoints" of these 15 homology segments and examine the sequence content and structure of the chromosome-rearrangement sites. Repeated sequences including clustered gene family members, LINE1, retrovirus sequences, and local duplications were found at all breakpoint sites. Results of this study indicate that, throughout evolution, "illegitimate" recombination (i.e., recombination of related DNA sequences at nonhomologous chromosomal sites) between gene families and other duplicated sequences has driven evolutionary changes in chromosome structure.

The JGI team is now extending these studies to comparisons of related regions in a nonmammalian vertebrate species, the chicken. Together with JGI's emerging sequence of the pufferfish and other vertebrate genomes being sequenced by public efforts worldwide, these studies will provide the basis for deeper evolutionary and functional studies of the estimated 1200 HSA19 genes. The resulting data and resources will be used to identify all HSA19 genes and their regulatory elements and pave the way for studies of biological function in model organisms. [Lisa Stubbs, DOE JGI and LLNL]

The electronic form of the newsletter may be cited in the following style:
Human Genome Program, U.S. Department of Energy, Human Genome News (v11n3-4).