Evolutionarily Conserved Sequences on Human Chromosome 21

Abstract

Comparison of human sequences with the DNA of other mammals is an excellent means of identifying functional elements in the human genome. Here we describe the utility of high-density oligonucleotide arrays as a rapid approach for comparing human sequences with the DNA of multiple species whose sequences are not presently available. High-density arrays representing ∼22.5 Mb of nonrepetitive human chromosome 21 sequence were synthesized and then hybridized with mouse and dog DNA to identify sequences conserved between humans and mice (human-mouse elements) and between humans and dogs (human-dog elements). Our data show that sequence comparison of multiple species provides a powerful empiric method for identifying actively conserved elements in the human genome. A large fraction of these evolutionarily conserved elements are present in regions on chromosome 21 that do not encode known genes.The identification of functional elements in the human DNA sequence is a major goal of genome research. Because sequences with function tend to be actively conserved through evolution whereas nonfunctional sequences diverge, comparison of human DNA with that of other species is a powerful method for identifying functional elements (Hardison et

Numerous potentially functional but non-genic conserved sequences on human chromosome 21

“…Here, we have compared the entire human chromosome 21 with syntenic regions of the mouse genome, and have identified a large number of conserved blocks of unknown function. Although previous studies have made similar observations 6,7 , it is unknown whether these conserved sequences are genes or not. Here we present an extensive experimental and computational analysis of human chromosome 21 in an effort to assign function to sequences conserved between human chromosome 21 (ref.…”

“…A preliminary description of sequence conservation along human chromosome 21 has been presented in previous studies 6,7 . These studies have detected patterns of conservation similar to our study, but the question of whether these unknown conserved sequences are unannotated genes or are non-genic remained unanswered.…”

“…One study used highdensity microarrays 6 , which provide qualitative but not reliable quantitative data in terms of numbers and types of substitutions at levels of divergence such as those between human and mouse. Another study performed nucleotide comparisons 7 , but the data were restricted to the degree of overlap of the conserved sequences with the known genes, and only involved two species.…”

“…We set out to analyse systematically the expression patterns of genes from an entire chromosome. We chose human chromosome 21 because of the medical relevance of trisomy 21 (Down's syndrome) 6 . Here we show the expression analysis of all identifiable murine orthologues of human chromosome 21 genes (161 out of 178 confirmed human genes) by RNA in situ hybridization on whole mounts and tissue sections, and by polymerase chain reaction with reverse transcription on adult tissues.…”

DNA sequence and comparative analysis of chimpanzee chromosome 22

“…HSA21 is one of the most well characterized human chromosomes 7,[12][13][14] and serves as a representative of the human genome by having characteristic features such as uneven distribution of GþC content with a high correlation to gene density, and repetitive/duplicated structures, allowing for detailed long-range comparative studies with PTR22. Moreover, molecular analysis of HSA21 and its genes is of central medical interest because of trisomy 21, the most common genetic cause of mental retardation in the human population.…”