Showing papers on "Pseudogene published in 1997"

The Evolution of Ribosomal DNA Divergent Paralogues and Phylogenetic Implications

Abstract: Although nuclear ribosomal DNA (rDNA) repeats evolve together through concerted evolution, some genomes contain a considerable diversity of paralogous rDNA. This diversity includes not only multiple functional loci but also putative pseudogenes and recombinants. We examined the occurrence of divergent paralogues and recombinants in Gossypium, Nicotiana, Tripsacum, Winteraceae, and Zea ribosomal internal transcribed spacer (ITS) sequences. Some of the divergent paralogues are probably rDNA pseudogenes, since they have low predicted secondary structure stability, high substitution rates, and many deamination-driven substitutions at methylation sites. Under standard PCR conditions, the low stability paralogues amplified well, while many high-stability paralogues amplified poorly. Under highly denaturing PCR conditions (i.e., with dimethylsulfoxide), both low- and high-stability paralogues amplified well. We also found recombination between divergent paralogues. For phylogenetics, divergent ribosomal paralogues can aid in reconstructing ancestral states and thus serve as good outgroups. Divergent paralogues can also provide companion rDNA phylogenies. However, phylogeneticists must discriminate among families of divergent paralogues and recombinants or suffer from muddled and inaccurate organismal phylogenies.

Cloning of a gene highly overexpressed in cancer coding for a novel KH-domain containing protein.

Abstract: In a previous large scale screen for differentially expressed genes in pancreatic cancer, we identified a gene highly overexpressed in cancer encoding a novel protein with four K-homologous (KH) domains. KH-domains are found in a subset of RNA-binding proteins, including pre-mRNA-binding (hnRNP) K protein and the fragile X mental retardation gene product (FMR1). By fluorescence in situ hybridization (FISH) the identified gene named koc (KH domain containing protein overexpressed in cancer) was assigned to chromosome 7p11.5. Two pseudogenes were localised on chromosome 6 and 11. The cloned koc cDNA has a 250 bp 5′-UTR, a 1740 bp ORF and a 2168 bp 3′-UTR. The AU-rich 3′-untranslated region of koc contains eight AUUUA and four AUUUUUA reiterated motifs. The deduced koc protein with 580 amino-acids has a relative molecular mass (Mr) of approximately 65 000 (65 K). The koc transcript is highly overexpressed in pancreatic cancer cell lines and in pancreatic cancer tissue as compared to both, normal pancreas and chronic pancreatitis tissue. High levels of expression were as well found in tissue samples of other human tumours. As the KH domain has been shown to be involved in the regulation of RNA synthesis and metabolism, we speculate that koc may assume a role in the regulation of tumour cell proliferation by interfering with transcriptional and or posttranscriptional processes. However, the precise role of koc in human tumour cells is unknown and remains to be elucidated.

One-megabase sequence analysis of the human immunoglobulin lambda gene locus.

Abstract: A total of 1,025,415 bases of nucleotide sequence, including the entire human immunoglobulin lambda gene locus has been determined. This is the largest contiguous human DNA sequence ever published. The sequence data revealed the organization of 36 potentially active V lambda gene segments, 33 pseudogene segments, and seven J lambda-C lambda gene segments. Among these 69 functional or nonfunctional V lambda gene segments, 32 were newly discovered. These V lambda gene segments are located within five gene-rich clusters and are divided into five clans based on sequence identity. Five potentially active nonimmunoglobulin genes were also detected within the lambda gene locus, and two other genes were observed in the upstream region. Sequence organization suggests that large DNA duplications diversified the germ-line repertoire of the V lambda gene segments.

Ancient mtDNA sequences in the human nuclear genome: A potential source of errors in identifying pathogenic mutations

Abstract: Nuclear-localized mtDNA pseudogenes might explain a recent report describing a heteroplasmic mtDNA molecule containing five linked missense mutations dispersed over the contiguous mtDNA CO1 and CO2 genes in Alzheimer's disease (AD) patients. To test this hypothesis, we have used the PCR primers utilized in the original report to amplify CO1 and CO2 sequences from two independent rho degrees (mtDNA-less) cell lines. CO1 and CO2 sequences amplified from both of the rho degrees cells, demonstrating that these sequences are also present in the human nuclear DNA. The nuclear pseudogene CO1 and CO2 sequences were then tested for each of the five "AD" missense mutations by restriction endonuclease site variant assays. All five mutations were found in the nuclear CO1 and CO2 PCR products from rho degrees cells, but none were found in the PCR products obtained from cells with normal mtDNA. Moreover, when the overlapping nuclear CO1 and CO2 PCR products were cloned and sequenced, all five missense mutations were found, as well as a linked synonymous mutation. Unlike the findings in the original report, an additional 32 base substitutions were found, including two in adjacent tRNAs and a two base pair deletion in the CO2 gene. Phylogenetic analysis of the nuclear CO1 and CO2 sequences revealed that they diverged from modern human mtDNAs early in hominid evolution about 770,000 years before present. These data would be consistent with the interpretation that the missense mutations proposed to cause AD may be the product of ancient mtDNA variants preserved as nuclear pseudogenes.

Design and testing of beta-actin primers for RT-PCR that do not co-amplify processed pseudogenes.

Abstract: Quantitative reverse transcription polymerase chain reaction (RT-PCR) is being used increasingly as an alternative to Northern blots analysis or RNase protection assays for quantitation of gene expression. To quantify different samples, measurements are often normalized using the expression of so-called "housekeeping" genes, such as cytoplasmic beta-actin or glyceraldehyde-3-phosphate dehydrogenase. This approach can produce false results because the presence of processed pseudogenes in the genome, which are related to some of the commonly used transcripts of housekeeping genes, leads to co-amplification of contaminating genomic DNA. By yielding amplification products of the same or similar size as the reverse-transcribed target, mRNA quantitation of expression is prone to error. In this paper, we report the results of using three sets of beta-actin primers for RT-PCR in the presence and absence of genomic DNA. In addition, we propose two new pairs of oligonucleotide primers that specifically amplify the human and rat beta-actin reverse-transcribed mRNA but not pseudogene sequences. These primers are especially suitable for quantitation of mRNA in small tissue samples (e.g., biopsies), where DNase digestion is not feasible, and therefore DNA contamination cannot be avoided.

Rates of nuclear and cytoplasmic mitochondrial DNA sequence divergence in mammals.

Abstract: Differential rates of nucleotide substitution among different gene segments and between distinct evolutionary lineages is well documented among mitochondrial genes and is likely a consequence of locus-specific selective constraints that delimit mutational divergence over evolutionary time. We compared sequence variation of 18 homologous loci (15 coding genes and 3 parts of the control region) among 10 mammalian mitochondrial DNA genomes which allowed us to describe different mitochondrial evolutionary patterns and to produce an estimation of the relative order of gene divergence. The relative rates of divergence of mitochondrial DNA genes in the family Felidae were estimated by comparing their divergence from homologous counterpart genes included in nuclear mitochondrial DNA (Numt, pronounced "new might"), a genomic fossil that represents an ancient transfer of 7.9 kb of mitochondrial DNA to the nuclear genome of an ancestral species of the domestic cat (Felis catus). Phylogenetic analyses of mitochondrial (mtDNA) sequences with multiple outgroup species were conducted to date the ancestral node common to the Numt and the cytoplasmic (Cymt) mtDNA genes and to calibrate the rate of sequence divergence of mitochondrial genes relative to nuclear homologous counterparts. By setting the fastest substitution rate as strictly mutational, an empirical "selective retardation index" is computed to quantify the sum of all constraints, selective and otherwise, that limit sequence divergence of mitochondrial gene sequences over time.

The α-gliadin gene family. II. DNA and protein sequence variation, subfamily structure, and origins of pseudogenes

Abstract: The derived amino-acid sequences of all reported α-gliadin clones are compared and analyzed, and the patterns of sequence change within the α-gliadin family are examined. The most variable sequences are two polyglutamine domains. These two domains are characteristic features of the α-gliadin storage proteins and account for most of the variation in protein size of this otherwise highly conserved protein family. In addition, their encoding DNA sequences form microsatellites. Single-base substitutions in the α-gliadin genes show a preponderance of transitions, including the C to T substitution which contributes to the generation of stop codons, and consequently to the observation that approximately 50% of the α-gliadin genes are pseudogenes. In one unusual gene, a microsatellite has expanded to 321 bp as compared to the normal 36–72 bp, and may result from similar mechanisms that produce polyglutamine-associated genetic diseases in humans. A comparison of the 27 reported sequences show several α-gliadin gene subfamilies, at least some of which are genome specific.

A p47-phox pseudogene carries the most common mutation causing p47-phox- deficient chronic granulomatous disease.

Abstract: The predominant genetic defect causing p47-phox-deficient chronic granulomatous disease (A47 degrees CGD) is a GT deletion (DeltaGT) at the beginning of exon 2. No explanation exists to account for the high incidence of this single mutation causing a rare disease in an unrelated, racially diverse population. In each of 34 consecutive unrelated normal individuals, both the normal and mutant DeltaGT sequences were present in genomic DNA, suggesting that a p47-phox related sequence carrying DeltaGT exists in the normal population. Screening of genomic bacteriophage and YAC libraries identified 13 p47-phox bacteriophage and 19 YAC clones. The GT deletion was found in 11 bacteriophage and 15 YAC clones. Only 5 exonic and 33 intronic differences distinguished all DeltaGT clones from all wild-type clones. The most striking differences were a 30-bp deletion in intron 1 and a 20-bp duplication in intron 2. These results provide good evidence for the existence of at least one highly homologous p47-phox pseudogene containing the DeltaGT mutation. The p47-phox gene and pseudogene(s) colocalize to chromosome 7q11.23. This close linkage, together with the presence within each gene of multiple recombination hot spots, suggests that the predominance of the DeltaGT mutation in A47 degrees CGD is caused by recombination events between the wild-type gene and the pseudogene(s).

The human histone gene cluster at the D6S105 locus.

Abstract: The sequences and organization of the histone genes in the histone gene cluster at the chromosomal marker D6S105 have been determined by analyzing the Centre d’Etude du Polymorphisme Humain yeast artificial chromosome (YAC) 964f1. The insert of the YAC was subcloned in cosmids. In the established contig of the histone-gene-containing cosmids, 16 histone genes and 2 pseudogenes were identified: one H1 gene (H1.5), five H2A genes, four H2B genes and one pseudogene of H2B, three H3 genes, and three H4 genes plus one H4 pseudogene. The cluster extends about 80 kb with a nonordered arrangement of the histone genes. The dinucleotide repeat polymorphic marker D6S105 was localized at the telomeric end of this histone gene cluster. Almost all human histone genes isolated until now have been localized within this histone gene cluster and within the previously described region of histone genes, about 2 Mb telomeric of the newly described cluster or in a small group of histone genes on chromosome 1. We therefore conclude that the data presented here complete the set of human histone genes. This now allows the general organization of the human histone gene complement to be outlined on the basis of a compilation of all known histone gene clusters and solitary histone genes.

Identification of Three Additional Genes Contiguous to the Glucocerebrosidase Locus on Chromosome 1q21: Implications for Gaucher Disease

Abstract: Gaucher disease results from the deficiency of the lysosomal enzyme glucocerebrosidase (EC 3.2.1.45). Although the functional gene for glucocerebrosidase (GBA) and its pseudogene (psGBA), located in close proximity on chromosome 1q21, have been studied extensively, the flanking sequence has not been well characterized. The recent identification of human metaxin (MTX) immediately downstream of psGBA prompted a closer analysis of the sequence of the entire region surrounding the GBA gene. We now report the genomic DNA sequence and organization of a 75-kb region around GBA, including the duplicated region containing GBA and MTX. The origin and endpoints of the duplication leading to the pseudogenes for GBA and MTX are now clearly established. We also have identified three new genes within the 32 kb of sequence upstream to GBA, all of which are transcribed in the same direction as GBA. Of these three genes, the gene most distal to GBA is a protein kinase (clk2). The second gene, propin1, has a 1.5-kb cDNA and shares homology to a rat secretory carrier membrane protein 37 (SCAMP37). Finally, cote1, a gene of unknown function lies most proximal to GBA. The possible contributions of these closely arrayed genes to the more atypical presentations of Gaucher disease is now under investigation.

Identification of a novel MHC class I gene, Mamu-AG, expressed in the placenta of a primate with an inactivated G locus.

Abstract: Maternal tolerance of the fetal allograft remains poorly understood. In humans, expression of the highly polymorphic classical HLA-A and HLA-B loci is suppressed, while expression of the nonclassical HLA-G locus is up-regulated at the maternal-fetal interface. Like other nonclassical MHC class I molecules, HLA-G exhibits limited diversity, but certain characteristics of HLA-G distinguish it from other nonclassical MHC class I molecules: it has a truncated cytoplasmic domain, it is the product of alternatively spliced mRNAs, and it is expressed primarily in the placenta. We have examined MHC class I expression in the placenta of the rhesus monkey to determine whether this animal is a suitable model in which to study the function of HLA-G. Although the rhesus monkey possesses orthologs of many MHC class I and II loci found in humans, the HLA-G ortholog is a pseudogene in this nonhuman primate species. In this study, we report the identification of a novel nonclassical MHC class I locus expressed in the placenta of the rhesus monkey, Mamu-AG (Macaca mulatta-AG). Although unrelated to HLA-G, Mamu-AG encodes glycoproteins with all of the characteristics of HLA-G. These Mamu-AG glycoproteins are limited in their diversity, possess truncated cytoplasmic domains, are the products of alternatively spliced mRNAs, and their expression is restricted to the placenta. Taken together, these data suggest that convergent evolution may have resulted in the expression of a unique nonclassical MHC class I molecule in the rhesus monkey placenta, and that the common structural features of Mamu-AG and HLA-G may be functionally significant.

Identification and characterization of a novel member of the EXT gene family, EXTL2.

Abstract: Recently, two homologous genes, EXT1 and EXT2, with a putative tumor suppressor function have been described. Mutations in both genes are responsible for multiple exostosis syndrome (EXT), an autosomal dominant condition characterized by the presence of multiple osteochondromas, bony excrescences that sometimes undergo malignant transformation to chondrosarcoma. This family of EXT genes has been extended by the identification of an EXT-like (EXTL) gene showing a high degree of homology with the EXT genes. We report here a second EXT-like gene (EXTL2) which is homologous to the EXT and EXTL genes. EXTL2 consists of 5 exons encoding an ubiquitously expressed protein of 330 amino acids. In addition, a putative pseudogene, EXTL2P was also identified. The EXTL2 gene was assigned to chromosome 1p11–p12, whereas EXTL2P was mapped on chromosome 2q24–q31.

The Human COX10 Gene is Disrupted During Homologous Recombination Between the 24 kb Proximal and Distal CMT1A-REPs

Abstract: The CMT1A-REPs are two large directly repeating DNA sequences located on chromosome 17p11.2-p12 flanking the region duplicated in patients with Charcot-Marie-Tooth disease type 1A (CMT1A) and deleted in patients with hereditary neuropathy with liability to pressure palsies (HNPP). We have sequenced two cosmids, c74F4 and c15H12, which contain the entire proximal and distal CMT1A-REPs and determined that these repeats are approximately 99% identical across a 24,011 bp region. In addition, both contain an exon of the human heme A:farnesyltransferase gene (COX10). Hybridization studies revealed that COX10 spans the distal CMT1A-REP, while the proximal CMT1A-REP contains an isolated COX10 'pseudo-exon'. There is also a COX10 hybridization signal on chromosome 10 which appears to represent a processed pseudogene. We propose that the distal CMT1A-REP represents the progenitor copy of COX10 exon VI which was duplicated with surrounding intronic sequences during mammalian genome evolution and that the HNPP deletion results in a COX10 null allele.

Mapping AAC1, AAC2 and AACP, the genes for arylamine N-acetyltransferases, carcinogen metabolising enzymes on human chromosome 8p22, a region frequently deleted in tumours

Abstract: Arylamine N-acetyltransferases (NATs) are encoded at two loci on 8p22, a region subject to deletions in bladder tumours. The two functional genes (AAC1 and AAC2 alias NAT1 and NAT2) without introns in the coding region, encode enzymes which metabolise carcinogens, including bladder carcinogens. They are both multi-allelic and certain alleles have been implicated as susceptibility factors in bladder cancer. There is a third N-acetyltransferase gene, a pseudogene, AACP alias NATP, which we show is also located on chromosome 8 at the p22 region. We have mapped a series of YAC clones (ICI and CEPH) containing the NAT genes and the markers D8S21, an RFLP marker, and D8S261, a microsatellite marker. We show that D8S21 is a portion of the coding region of AAC2. The order of genes in this region, covering some 2 Mb, is TEL-D8S261-AAC1-AACP-AAC2 (D8S21)-CEN. The restriction map also illustrates that there are likely to be other expressed genes in the region through the identification of CpG islands.

The nucleotide sequence of Saccharomyces cerevisiae chromosome XIV and its evolutionary implications.

Abstract: In 1992 we started assembling an ordered library of cosmid clones from chromosome XIV of the yeast Saccharomyces cerevisiae. At that time, only 49 genes were known to be located on this chromosome and we estimated that 80% to 90% of its genes were yet to be discovered. In 1993, a team of 20 European laboratories began the systematic sequence analysis of chromosome XIV. The completed and intensively checked final sequence of 784,328 base pairs was released in April, 1996. Substantial parts had been published before or had previously been made available on request. The sequence contained 419 known or presumptive protein-coding genes, including two pseudogenes and three retrotransposons, 14 tRNA genes, and three small nuclear RNA genes. For 116 (30%) protein-coding sequences, one or more structural homologues were identified elsewhere in the yeast genome. Half of them belong to duplicated groups of 6-14 loosely linked genes, in most cases with conserved gene order and orientation (relaxed interchromosomal synteny). We have considered the possible evolutionary origins of this unexpected feature of yeast genome organization.

Alternate paths of evolution for the photosynthetic gene rbcL in four nonphotosynthetic species of Orobanche.

Abstract: We have determined the nucleotide sequence for the Rubisco large subunit from four holoparasitic species of Orobanche. Intact open reading frames are present in two species (O. corymbosa and O. fasciculata), whereas the remaining species (O. cernua and O. ramosa) have rbcL pseudogenes. Sequences for rbcL 5'-UTRs from species of Orobanche have few changes in the promoter and ribosome binding sites compared to photosynthetic higher plants. Comparison of rbcL 3'-UTR sequences for Nicotiana, Ipomoea, Cuscuta, and Orobanche reveal that nucleotide sequences from parasitic plants have regions capable of forming stem-loop structures, but 56–69 nt are deleted upstream of the stem-loop in the parasitic plants compared to their photosynthetic relatives. Although rbcL pseudogenes of O. cernua and O ramosa have many large and small deletions, few indels are shared in common, implying that their common ancestor probably had an intact rbcL reading frame. Intact rbcL reading frames in O. corymbosa and O. fasciculata retain a bias of synonymous over nonsynonymous substitutions and deduced protein sequences are consistent with potentially functional Rubisco large subunit proteins. A conservative model of random substitution processes in pseudogene sequences estimates that the probability is low (P<0.028) that these sequences would retain an open reading frame by chance. Species of Orobanche have either had recent photosynthetic ancestors, implying multiple independent losses of photosynthesis in this genus, or the rbcL gene may serve an unknown function in some nonphotosynthetic plants.

Mutation Pattern Variation Among Regions of the Primate Genome

Abstract: We sequenced three argininosuccinate-synthetase-processed pseudogenes (PsiAS-A1, PsiAS-A3, PsiAS-3) and their noncoding flanking sequences in human, orangutan, baboon, and colobus. Our data showed that these pseudogenes were incorporated into the genome of the Old World monkeys after the divergence of the Old World and New World monkey lineages. These pseudogene flanking regions show variable mutation rates and patterns. The variation in the G/C to A/T mutation rate (u) can account for the unequal GC contents at equilibrium: 34.9, 36.9, and 41.7% in the pseudogene PsiAS-A1, PsiAS-A3, and PsiAS-3 flanking regions, respectively. The A/T to G/C mutation rate (v) seems stable and the u/v ratios equal 1.9, 1.7, and 1.4 in the flanking regions of PsiAS-A1, PsiAS-A3, and PsiAS-3, respectively. These "regional" variations of the mutation rate affect the evolution of the pseudogenes, too. The ratio u/v being greater than 1.0 in each case, the overall mutation rate in the GC-rich pseudogenes is, as expected, higher than in their GC-poor flanking regions. Moreover, a "sequence effect" has been found. In the three cases examined u and v are higher (at least 20%) in the pseudogene than in its flanking region-i.e., the pseudogene appears as mutation "hot" spots embedded in "cold" regions. This observation could be partly linked to the fact that the pseudogene flanking regions are long-standing unconstrained DNA sequences, whereas the pseudogenes were relieved of selection on their coding functions only around 30-40 million years ago. We suspect that relatively more mutable sites maintained unchanged during the evolution of the argininosuccinate gene are able to change in the pseudogenes, such sites being eliminated or rare in the flanking regions which have been void of strong selective constraints over a much longer period. Our results shed light on (1) the multiplicity of factors that tune the spontaneous mutation rate and (2) the impact of the genomic position of a sequence on its evolution.

Structural and Evolutionary Studies on Sterol 14-Demethylase P450 (CYP51), the Most Conserved P450 Monooxygenase: II. Evolutionary Analysis of Protein and Gene Structures.

Abstract: Phylogenetic analyses based on protein sequence data indicated that sterol 14-demethylase P450 (CYP51) and bacterial CYP51-like protein were joined into a distinctive evolutionary cluster, CYP51 cluster, within the CYP protein superfamily. The most probable branch topology of the CYP51 phylogenetic tree was (bacteria, (plants, (fungi, mammals))), which is comparable to the phylogeny of major kingdoms of living matter, suggesting that CYP51 has been conserved from the era of prokaryotic evolution. This may be strong evidence supporting the prokaryotic origin of P450. Structure of flanking regions and the number and insertion sites of introns are quite different between mammalian and fungal CYP51s. This fact indicates that different mechanisms are operative in evolution of protein sequences and gene structures. CYP51 is the first example violating the well-documented rule that the basic structure of a gene, including intron insertion sites, is well conserved in each P450 family. One CYP51 processed a pseudogene was found in rat genome. Nonsynonymous nucleotide divergence observed between the pseudogene and CYP51 cDNA was less than one-fifth of the synonymous divergence. This unusually low rate of nonsynonymous nucleotide changes in the pseudogene suggests that it may be derived from another CYP51, which might have been active for a significant duration in the past.

Mutation-haplotype analysis of steroid 21-hydroxylase (CYP21) deficiency in Finland. Implications for the population history of defective alleles

Abstract: Congenital adrenal hyperplasia (CAH) due to steroid 21-hydroxylase deficiency is a common inherited defect of adrenal steroid hormone biosynthesis. Unusually for genetic disorders, the majority of mutations causing CAH apparently result from recombinations between the CYP21 gene encoding the 21-hydroxylase enzyme and the closely linked, highly homologous pseudogene CYP21P. The CYP21 and CYP21P genes are located in the major histocompatibility complex class III region on chromosome 6p21.3. We analyzed the mutations and recombination breakpoints in the CYP21 gene and determined the associated haplotypes in 51 unrelated Finnish families with CAH. They represent no less than half of all CYP21 deficiency patients in Finland. The results indicate the existence of multiple founder mutation-haplotype combinations in the population of Finnish CAH patients. The three most common haplotypes constituted half of all affected chromosomes; only one-sixth of the haplotypes represented single cases. Each of the common haplotypes was shown consistently to carry a typical CYP21 mutation and only in some cases was additional variation observed. Surprisingly, comparisons with previous published data revealed that several of the frequent mutation-haplotype combinations in Finland are in fact also found in many other populations of patients of European origin, thus suggesting that these haplotypes are of ancient origin. This is in clear contrast to many reports, including the present one, where a high frequency of de novo mutations in the CYP21 gene has been reported. In addition, two unique sequence aberrations in CYP21 (W302X and R356Q), not known to exist in the CYP21P pseudogene, were detected.

Molecular Evolution of Cytochrome c Oxidase Subunit IV: Evidence for Positive Selection in Simian Primates

Abstract: Cytochrome c oxidase (COX) is a multi- subunit enzyme complex that catalyzes the final step of electron transfer through the respiratory chain on the mitochondrial inner membrane. Up to 13 subunits en- coded by both the mitochondrial (subunits I, II, and III) and nuclear genomes occur in eukaryotic organisms ranging from yeast to human. Previously, we observed a high number of amino acid replacements in the human COX IV subunit compared to mouse, rat, and cow or- thologues. Here we examined COX IV evolution in the two groups of anthropoid primates, the catarrhines (hominoids, cercopithecoids) and platyrrhines (ceboids), as well as one prosimian primate (lorisiform), by se- quencing PCR-amplified portions of functional COX4 genes from genomic DNAs. Phylogenetic analysis of the COX4 sequence data revealed that accelerated nonsyn- onymous substitution rates were evident in the early evo- lution of both catarrhines and, to a lesser extent, platyr- rhines. These accelerated rates were followed later by decelerated rates, suggesting that positive selection for adaptive amino acid replacement became purifying se- lection, preserving replacements that had occurred. The evidence for positive selection was especially pro- nounced along the catarrhine lineage to hominoids in which the nonsynonymous rate was first faster than the synonymous rate, then later much slower. The rates of three types of ''neutral DNA'' nucleotide substitutions (synonymous substitutions, pseudogene nucleotide sub- stitutions, and intron nucleotide substitutions) are similar and are consistent with previous observations of a slower rate of such substitutions in the nuclear genomes of hominoids than in the nuclear genomes of other primate and mammalian lineages.