Published online before print
February 12, 2003, 10.1101/gr.554603
Vol 13, Issue 3, 341-346, March 2003
Genomic DNA Insertions and Deletions Occur Frequently Between Humans and Nonhuman Primates
Kelly A. Frazer1,
Xiyin Chen,
David A. Hinds,
P.V. Krishna Pant,
Nila Patil and
David R. Cox
Perlegen Sciences, Mountain View, California 94043, USA
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ABSTRACT
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Comparative DNA sequence studies between humans and nonhuman
primates will be important for understanding the genetic basis of the
phenotypic differences between these species. Here we compare  27 Mb
of human chromosome 21 with chimpanzee DNA sequences identifying 57
genomic rearrangements (deletions and insertions ranging in size from
0.2 to 8.0 kb) between the two species. These rearrangements are
distributed along the entire length of chromosome 21, with 35%
found in genomic intervals encoding genes (genic intervals), and have
occurred in the genomes of both humans and chimpanzees. Comparison of
9 Mb of human chromosome 21 with orangutan, rhesus macaque, and
woolly monkey DNA sequences identified a combined total of 114 genomic
rearrangements between humans and nonhuman primates. Analysis of these
rearrangements revealed that they are randomly distributed with respect
to genic and nongenic intervals and identified one deletion that has
likely resulted in the inactivation of a gene
( 1,3-galactosyltransferase) in the woolly monkey. Our data show that
genomic rearrangements have occurred frequently during primate genome
evolution and significantly contribute to the DNA differences between
these species. These DNA rearrangements are commonly found in genic
intervals, and thus provide natural starting points for focused
investigations of qualitative and quantitative gene expression
differences between humans and other
primates.
[Supplemental material is available online at
www.genome.org.]
Numerous comparative sequence studies have demonstrated that there
is more similarity at the nucleotide level between
humans and chimpanzees than between humans and any other species (King
and Wilson 1975 ; Hacia 2001). Thus, identifying the types and extent of
DNA sequence variation existing between humans and chimpanzees will be
important for understanding the genetic basis of recently evolved,
human-specific traits (Gagneux and Varki 2001). Previous comparative
studies, focused on analyzing the differences between aligned human and
chimpanzee sequences (single-nucleotide fixed differences), have
indicated that the two species are 98.4%–98.8% identical at the
nucleotide level (Koop et al. 1989; Chen and Li 2001; Fujiyama et al.
2002). The 1.5% single-nucleotide fixed differences have, to date,
been the primary focus of studies aimed at understanding the biological
differences, resulting from qualitative and quantitative differential
gene expression, between humans and chimpanzees. It was demonstrated
previously that large-scale segmental duplications (>400 kb; Bailey et
al. 2002), pericentric inversions (Nickerson and Nelson 1998), and
chromosomal fusions (Yunis and Prakash 1982) occurring after the
separation of humans and chimpanzees from their common evolutionary
ancestor resulted in DNA differences between the two species. Several
human–chimpanzee comparative sequence analyses have suggested that
smaller-sized rearrangements may also exist between human and
chimpanzee DNA (Ueda et al. 1990; Fujiyama et al. 2002). However, the
extent and significance of DNA sequence differences between humans and
chimpanzees due to these smaller-sized genomic rearrangements are
poorly characterized. Furthermore, the size, chromosomal distribution
across gene-rich and gene-poor intervals, and evolutionary history of
these genomic rearrangements have not yet been systematically examined.
We recently demonstrated that human high-density oligonucleotide arrays
provide a rapid and effective tool for comparing human sequences with
the DNA of other mammalian species (Frazer et al. 2001). We previously
performed a cross-species comparative sequence analysis of human
chromosome 21 by hybridizing mouse and dog bacterial artificial
chromosome (BAC) DNA to human 21q arrays in order to identify
evolutionarily conserved elements. In this report we describe the use
of human high-density arrays for large-scale comparisons of human
sequences with those of nonhuman primates to identify genomic
rearrangements that result in DNA sequence differences between the
species.
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RESULTS AND DISCUSSION
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Amplification of Chimpanzee Sequences
Here we compare human chromosome 21 with the syntenic chimpanzee
sequences (i.e., chimpanzee chromosome 22) to characterize the genomic
rearrangements that contribute to DNA differences between the two
species. To obtain chimpanzee sequences, we took advantage of a set of
paired polymerase chain reaction (PCR) primers which were designed to
amplify minimally overlapping 10 kb long-range (LR)-PCR products
spanning the entire length (32.4 Mb) of human chromosome 21 (Patil
et al. 2001). The high level of nucleotide similarity between human and
chimpanzee DNA allowed us to use this set of paired PCR primers
designed based on human chromosome 21 sequences to efficiently amplify
chimpanzee chromosome 22 sequences by LR-PCR (Fig.
1A). Of a total of 3110 paired PCR primers
that successfully amplified LR-PCR products from human DNA, 2957
amplified LR-PCR products from chimpanzee DNA, resulting in the
comparative analysis of 27 Mb of human chromosome 21 and chimpanzee
chromosome 22 sequences.
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Figure 1. Analysis of syntenic human and chimpanzee LR-PCR products for deletions
and insertions. (A) The lengths of syntenic human (H) and
chimpanzee (C) LR-PCR products are compared by gel electrophoresis.
Syntenic LR-PCR products are the same length (lane 6)
indicating that no rearrangement is present, longer in humans than in
the chimpanzees (lanes 1–4), indicating that the
chimpanzee sequence is deleted with respect to the human sequence, or
longer in the chimpanzee than in human (lane 7), indicating
that the chimpanzee sequence contains an insertion relative to the
human sequence. LR-PCR product #1 corresponds to the rearrangement in
Segment 32 at 320 kb as given in Suppl. Table 1, #2 = Segment 36 at 28
kb, #3 = Segment 71 at 234 kb, #4 = Segment 77 at 125 kb, and #7 =
Segment 2 at 292 kb. (B) The human and chimpanzee LCR-PCR
products shown in (A) were hybridized to the 21q arrays, and
their percent conformance (vertical axis), which is a measure of their
similarity (Frazer et al. 2001), was plotted relative to their position
in the human reference sequence (horizontal axis). Each tick mark in
the scale represents a 1-kb interval. The sequence positions of the PCR
products in (A) and (C) are indicated by horizontal
lines. The overlap of the LR-PCR products in (A) with
neighboring chromosome 21 LR-PCR products is shown. The sharp drop in
conformance values (yellow circles) indicates the positions of the
sequences deleted in the chimpanzee LR-PCR products 1–5 in
(A). Sequences with absent conformance information, such as
those indicated by black arrows, correspond to interspersed repeats,
which were not tiled on the 21q arrays (see Methods). LR-PCR product #1
is the only fragment in which two localized deletions account for a
size difference between chimpanzees and humans. For LR-PCR product #5,
the variation in the sizes of the human and chimpanzee bands is not
detectable on the gel but the deletion is evident in the comparative
21q array data. (C) Paired PCR primers designed to
the sequences flanking the deletions in LR-PCR products 1–5 in
(A) as shown in (B) were used to amplify human and
chimpanzee DNA. The lengths of the human vs. chimpanzee PCR products
provide more precise information about the deletion sizes (in bp).
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Comparison of Syntenic Human and Chimpanzee LR-PCR Products
Our initial analysis consisted of comparing the lengths of the
syntenic human and chimpanzee LR-PCR products by sizing them using
agarose gel electrophoresis (Fig. 1A). Although the majority of the
syntenic human and chimpanzee LR-PCR products have identical lengths,
33 have a difference in size ranging from 1 kb to 8 kb as determined
by inspection of the gels (Supplemental Table 1). Of the syntenic
LR-PCR products with different lengths, 27 were shorter and six were
longer in the chimpanzee, suggesting that the chimpanzee DNA sequences
contained deletions and insertions, respectively, relative to the human
DNA sequences.
High-Density Arrays Are an Effective Method for Detecting DNA Rearrangements
To determine whether the shorter-length chimpanzee LR-PCR products
contain a single localized deletion or numerous small dispersed
deletions, we examined the amplified chimpanzee DNA by hybridizing to a
series of high-density oligonucleotide arrays containing probes for
most of the unique sequences from human chromosome 21 (Hacia et al.
1998, 1999; Frazer et al. 2001). This analysis revealed that the
majority of chimpanzee LR-PCR products that are shorter in length than
their syntenic human counterparts contain a single localized deletion
(Suppl. Table 1). Inspection of the human–chimpanzee sequence
deletions, which are detected in the comparative 21q array data by a
sharp decrease in the conformance rate within the boundaries of a
chimpanzee LR-PCR product (Fig. 1B), determined that they are comprised
of varying percentages of unique and repetitive sequences (Fig. 1B),
and that most of the deletions result in the loss of some sequences
that are unique in the human genome (Suppl. Table 1). These results are
the first direct evidence that the human genome contains intervals
several kilobases in length that are comprised largely of unique
sequences, and which are not present in the syntenic regions of the
chimpanzee genome.
We next examined the comparative human–chimpanzee 21q array data to
determine whether we could identify the presence of additional
deletions in the amplified chimpanzee sequences. We searched for the
deletion signature in the array data—a sharp decrease in the
conformance rate—and found 24 such intervals (0.2–3.0 kb in
length) that had not been detected by LR-PCR product size variations on
gels (Suppl. Table 1). To demonstrate that these intervals of low
conformance on the human chromosome 21 arrays correspond to sequence
deletions on chimpanzee chromosome 22, we designed paired PCR primers
to sequences bordering five of the intervals and compared the lengths
of PCR products amplified from human and chimpanzee genomic DNA (Fig.
1C). In all cases, the syntenic human PCR product was longer than the
chimpanzee PCR product by the approximate basepair amount predicted by
the comparative 21q array data. These data indicate that comparative
analysis of human and chimpanzee DNA using high-density arrays is an
effective method for identifying intervals in the human genome
containing unique sequences that are missing in the syntenic regions of
the chimpanzee genome.
Genomic Rearrangements Account for a Significant Fraction of the DNA Sequence Differences Between Humans and Chimpanzees
In the 27 Mb segment of chromosome 21 analyzed, genomic DNA
rearrangements account for 0.6% (161 kb) basepair differences
between the human and chimpanzee syntenic sequences (Suppl. Fig. 1), of
which 82% correspond to 51 sequence deletions and 18%
correspond to six sequence insertions in the chimpanzee DNA (Suppl.
Table 1). Our observation that deletions are more prevalent than
insertions is due at least in part to an ascertainment bias, based on
the fact that insertions are only detectable by variation in the
size of the LR-PCR products on gels, whereas deletions are identified
by both size variations on gels and the comparative 21q array data.
Rearrangements smaller and larger in size than the detectable range
in this study (0.1–10.0 kb, see Methods) are likely to also be
present, and thus our data represent the minimal amount of basepair
differences between the syntenic human chromosome 21 and chimpanzee
chromosome 22 sequences due to insertions and deletions. These results
suggest that genomic rearrangements are responsible for a significant
fraction of the DNA sequence differences between humans and
chimpanzees, accounting for 50% as much DNA variation as
single-nucleotide fixed differences.
Characterization of Human Sequences at the Boundaries of DNA Rearrangements
We inspected the nucleotide sequences at the boundaries of the
human–chimpanzee deletions to ascertain whether a molecular mechanism
could be proposed to explain the frequency and distribution of these
rearrangements. This analysis revealed that both unique as well as a
variety of repetitive sequences are present at the deletion boundaries
in the human genome (Suppl. Table 2). These data neither implicate a
particular class of sequences nor indicate an obvious mechanism that
gives rise to these rearrangements, but suggest that they may be the
result of a stochastic process.
DNA Rearrangements Have Occurred in Both Humans and Chimpanzees
To elucidate whether the 57 genomic rearrangements observed in the
human–chimpanzee comparative analysis are the result of deletions and
insertions occurring predominately in one or the other of these
primates, we used the orangutan as an outgroup. For 16 of the
human–chimpanzee rearrangements, we were able to ascertain whether or
not the orangutan also had the rearrangement by examining both relative
sizes of the corresponding syntenic human, chimpanzee, and orangutan
LR-PCR products and comparative human–orangutan 21q array data (Suppl.
Table 3). Based on these data we determined for each of these
rearrangements whether it occurred in the human genome (the chimpanzee
and orangutan LR-PCR products are the same) or the chimpanzee genome
(the human and orangutan LR-PCR products are the same; Fig.
2). Of the 16 rearrangements that we
examined, five occurred in the human genome (three insertions and two
deletions) and 11 occurred in the chimpanzee genome (10 deletions and
one insertion; Suppl. Table 3). The fact that a greater number of
deletions than insertions are identified in the chimpanzee lineage is
likely to be at least in part due to our ascertain bias for
finding deletions with respect to human chromosome 21 sequences. These
data indicate that genomic DNA deletions and insertions have occurred
in both the human and chimpanzee genomes.
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Figure 2. The relative sizes of the syntenic human (H), chimpanzee (C), and
orangutan (O) LR-PCR products were used to determine whether the
rearrangement occurred in the human or chimpanzee genome and whether it
was an insertion or deletion event. (A) The relative sizes of
syntenic human, chimpanzee, and orangutan LR-PCR products compared
using gels. (B) The size variation of the human insertion in
(A) is barely detectable on gels but is evident in the
comparative 21q array data. These LR-PCR products correspond to the
rearrangements in Suppl. Table 2 as follows: human insertion = Segment
10 at 161 kb, human deletion = Segment 2 at 301 kb, chimpanzee
insertion = Segment 12 at 278 kb, chimpanzee deletion = Segment 76 at
51 kb.
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Distribution of Human–Chimpanzee DNA Rearrangements on Chromosome 21
To determine the spatial distribution of the human–chimpanzee
rearrangements, we divided chromosome 21 into 132 adjacent 250-kb
intervals and determined the number of genomic rearrangements mapping
within each interval (Fig. 3). A
statistical analysis revealed that the rearrangements are randomly
distributed along the entire length of chromosome 21, except for one
250-kb interval which contains an increased number of rearrangements
(P < 0.01). To further investigate the spatial distribution
of diverged human–chimpanzee sequences, we looked at the distribution
of 76 paired PCR primers that amplified LR-PCR products from human but
not chimpanzee DNA. The fact that these paired PCR primers (designed
based on human sequence) specifically fail to amplify LR-PCR products
from chimpanzee DNA suggests that their corresponding sequences have
either been rearranged or have significantly diverged in the chimpanzee
genome. Thus, looking at the distribution of these chimpanzee-specific
LR-PCR failures is an indirect way of identifying regions containing
either a genomic rearrangement or high sequence divergence. In
agreement with the distribution analysis of the genomic rearrangements,
the paired PCR primers corresponding to chimpanzee-specific LR-PCR
failures are randomly distributed in the 250-kb intervals on chromosome
21, except for two intervals that contain increased LR-PCR failures
(P < 0.0005; Fig. 3). Interestingly, the three 250-kb
intervals that we identified which contain an increased number of
rearrangements and/or an increased amount of sequence divergence are
clustered within an 1-Mb gene-poor region on chromosome 21 (Hattori
et al. 2000). These findings are consistent with a previous comparative
analysis of human chromosome 21 with chimpanzee sequences (based on
analyzing paired PCR primers that amplify human but not chimpanzee DNA;
Fujiyama et al. 2002). Our data indicate that the majority of genomic
DNA rearrangements are randomly distributed; however, a gene-poor
region on chromosome 21 contains an increased number of rearrangements
and/or a greater amount of sequence divergence than is expected by
chance.
DNA Rearrangements Are Commonly Located in Genic Intervals
To identity human–chimpanzee rearrangements with possible
functional consequences, we examined their distribution with respect to
chromosome 21 genic and nongenic intervals. Genic intervals (13.0
Mb) were defined as all sequences contained within 10 kb upstream to 10
kb downstream of the 216 annotated genes (Frazer et al. 2001), and
nongenic sequences (20.9 Mb) were defined as all other sequences on
human chromosome 21. Twenty of the rearrangements mapped into genic
intervals, of which 13 deleted intronic sequences of known genes, and
37 mapped into nongenic intervals. These data indicate that deletions
and insertions occur at relatively equal frequencies in genic and
nongenic intervals. The fact that the observed genomic rearrangements
are commonly located within and near the vicinity of genes implicates
that they may play a larger role than previously recognized in the
differential expression of certain genes between humans and
chimpanzees.
Comparison of Human Chromosome 21 With Other Nonhuman Primate Sequences
To further examine the frequency of deletions and insertions between
humans and nonhuman primates and the percentage of these rearrangements
located within genes, we targeted two intervals, each 4.5 Mb in
length and combined representing 27% of chromosome 21 sequences,
for comparative analysis with three additional primates (Fig. 3). Our
efforts resulted in the comparison of 5.7 Mb (63%), 4.2 Mb
(46%), and 3.7 Mb (41%) of the targeted human chromosome 21
sequences with orangutan (a great ape), rhesus macaque (an old world
monkey), and woolly monkey (a new world monkey) syntenic sequences,
respectively (Suppl. Fig. 1A; Suppl. Table 4). Interestingly, analysis
of the 114 identified genomic DNA rearrangements (the combined total
for the chimpanzee, orangutan, rhesus macaque, and woolly monkey
comparative analyses in the two targeted regions) revealed that 9%
of chromosome 21 DNA is deleted in at least one nonhuman primate
(Suppl. Fig. 1B). Of these genomic rearrangements, 35% are located
in genic regions, and one deletion observed in the human–woolly monkey
comparative analysis results in the loss of three alternatively spliced
exons of a gene encoding an enzyme, 1,3-galactosyltransferase-T5
(3Gal-T5; Fig. 4).
3Gal-T5 is involved in the synthesis of a cell-surface
epitope which is frequently used for the clinical diagnosis of cancer
in humans (Isshiki et al. 1999). These results indicate that genomic
DNA rearrangements occur frequently between humans and nonhuman
primates, and further support the supposition that they may play a
larger role than previously recognized in gene expression differences
between the species.
Conclusions
It has long been postulated that qualitative and quantitative
expression differences of genes will be found responsible for the
major biological differences between humans and chimpanzees (King and
Wilson 1975). To date, it has commonly been thought that
single-basepair changes between the human and chimpanzee genomes would
underlie the majority of these postulated regulatory differences.
However, the data we present in this study demonstrate that genomic
rearrangements are a significant source of DNA variation between humans
and chimpanzees, as well as other nonhuman primates. These
rearrangements provide excellent starting points for focused studies of
gene expression differences in humans and chimpanzees as part of an
effort to identify the genetic differences responsible for the
biological, physiological, and behavior differences between these
species.
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METHODS
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Amplification of Nonhuman Primate Sequences by LR-PCR
LR-PCR reactions were performed using genomic chimpanzee DNA
(Coriell Repository No. NG06939), orangutan DNA (Coriell Repository No.
NG12256), rhesus macaque DNA (Coriell Repository No. NG07109), and
woolly monkey DNA (Coriell Repository No. NG05356) as described (Patil
et al. 2001) using PCR primer pairs designed based on human chromosome
21 sequences. Initially, 153 of the 3110 paired chromosome 21 PCR
primers amplified LR-PCR products from human but not chimpanzee DNA.
After retesting, 76 of these primer pairs were again only successful
for human DNA, indicating that they specifically fail to amplify LR-PCR
products from chimpanzee DNA. For the orangutan, rhesus macaque, and
woolly monkey comparative analysis, 429 paired PCR primers were used to
amplify Region A (located on chromosome 21 from 0 to 4.6 Mb from the
centromeric end), and 432 paired PCR primers were used to amplify
Region B (located 22.6 to 27.1 Mb from the centromeric end).
Identification of DNA Rearrangements by Agarose Gel Electrophoresis
Visual inspection of the gels allowed us to detect deletions and
insertions ranging from 1 kb to 10 kb in size. Due to the large size
of the LR-PCR products (average length 10 kb), genomic
rearrangements smaller than 1 kb in length would result in size
variations between the syntenic human and nonhuman primate sequences
too small to detect by gels. In contrast, deletions in the nonhuman
primate genomes greater than 10 kb in length are not detected
because the LR-PCR products are not amplified (the paired PCR primers
are designed based on human sequence).
Identification of DNA Rearrangements Using Human 21q High-Density Arrays
The 21q high-density arrays consist of a series of eight wafer
designs, on which each of the unique chromosome 21 bases is
interrogated by eight unique oligonucleotides (25-mers) as described
(Frazer et al. 2001; Patil et al. 2001). The nonhuman primate LR-PCR
products were pooled based on the syntenic human chromosome 21
sequences represented on each of the 21q high-density arrays, and
hybridized as a single reaction as described (Patil et al. 2001). When
the probe complementary to the human reference sequence had greater
fluorescent intensity than the corresponding noncomplementary probes
(these probes differ from the complementary probe only at the 13th
position basepair), the nucleotide under interrogation was referred to
as conforming to the human reference sequence. To calculate the
"conformance rate", we looked at 30-nucleotide (nt)-length windows
and averaged the conformance of the individual nucleotides. For
example, if 27 of the 30 nucleotides conformed to the human reference
sequence, the window would have a 90% conformance rate (Frazer et al.
2001). The ability to confidently correlate a decreased "conformance
rate" within a LR-PCR product with a sequence deletion results in the
inability to detect deletions less than 100 bp in length. Because
only unique human sequences are tiled on the 21q arrays, sequence
deletions solely encompassing interspersed repeats are not detected in
the comparative 21q array data. DNA rearrangements identified by LR-PCR
products that are longer in nonhuman primates than in humans are also
not detected by analysis of the comparative 21q array data.
Chromosomal Distribution Analysis of DNA Rearrangements
To determine the expected distribution of the 57 human–chimpanzee
rearrangements, we performed 10,000 simulations in which we randomly
distributed 57 rearrangements among our 250-kb intervals, and counted
the frequency of multiple rearrangements in the same interval. In our
data, there is one 250-kb interval containing five rearrangements. In
the simulations, the probability of seeing five or more rearrangements
in one interval was about 0.01. A similar analysis for the distribution
of the 76 human-specific LR-PCR products was performed. We observed two
250-kb intervals containing seven human-specific LR-PCR products; the
probability of seeing this in the simulations was 0.0005.
Characterization of Human–Chimpanzee DNA Rearrangements in Genic Intervals
Of the 20 rearrangements mapping within genic intervals, 13 were
located in the introns of 12 genes (USP25, NCAM2, PRED16, APP, PRED29,
PRED33, IL10RB, KCNJ15, DSCAM, ERG, C21orf1, and ADARB1) and deleted
exonic sequences of two predicted genes (PRED16 and PRED58), whereas
seven were located within 10 kb upstream or downstream of seven genes
(CLDN17, KCNE2, C21orf5, PRED47, CSTB, COL6A1, and COL6A2).
Analysis of DNA Rearrangements in Targeted Chromosome 21 Intervals A and B
For two chromosome 21 intervals, each 4.5 Mb in length, human
sequences were compared with chimpanzee, orangutan, rhesus macaque, and
woolly monkey DNA. The total number of chromosome 21 basepairs in these
two intervals that are present in humans and absent in one of the
nonhuman primates or vice versa was calculated as follows: the lengths
of the deletions and insertions (in bp) observed in the nonhuman
primate divided by the total number of bp analyzed in the nonhuman
primate (Suppl. Figure 1). To calculate the percent of chromosome 21 bp
that are present in human but absent in at least one nonhuman primate
or vice versa (the combined total for the chimpanzee, orangutan, rhesus
macaque, and woolly monkey comparative analyses), we adjusted for
deletions and insertions that are shared.
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Acknowledgements
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We thank Curtis Kautzer for expert technical assistance and Dennis
Ballinger for critical reading of the manuscript. This work was
supported in part by the following grant: NIH GM-5748202 (K.A.F.).
The publication costs of this article were defrayed in part by payment
of page charges. This article must therefore be hereby marked
"advertisement" in accordance with 18 USC section 1734 solely to
indicate this fact.
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Footnotes
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1 Corresponding author. 
E-MAIL kelly_frazer{at}perlegen.com; FAX (650) 625-4510.
Article and publication are at
http://www.genome.org/cgi/doi/10.1101/gr.554603. Article published online before print in February
2003.
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REFERENCES
|
|---|
Bailey, J.A., Yavor, A.M., Viggiano, L., Misceo, D., Horvath, J.E., Archidiacono, N., Schwartz, S., Rocchi, M., and Eichler, E.E. 2002. Human-specific duplication and mosaic transcripts: The recent paralogous structure of chromosome 22. Am. J. Hum. Genet. 70: 83-100.[CrossRef][Medline]
Chen, F.C. and Li, W.H. 2001. Genomic divergences between humans and other hominoids and the effective population size of the common ancestor of humans and chimpanzees. Am. J. Hum. Genet. 68: 444-456.[CrossRef][Medline]
Frazer, K.A., Sheehan, J.B., Stokowski, R.P., Chen, X., Hosseini, R., Cheng, J.F., Fodor, S.P., Cox, D.R., and Patil, N. 2001. Evolutionarily conserved sequences on human chromosome 21. Genome Res. 11: 1651-1659.[Abstract/Free Full Text]
Fujiyama, A., Watanabe, H., Toyoda, A., Taylor, T.D., Itoh, T., Tsai, S.F., Park, H.S., Yaspo, M.L., Lehrach, H., Chen, Z., et al. 2002. Construction and analysis of a human-chimpanzee comparative clone map. Science 295: 131-134.[Abstract/Free Full Text]
Gagneux, P. and Varki, A. 2001. Genetic differences between humans and great apes. Mol. Phylogenet. Evol. 18: 2-13.[CrossRef][Medline]
Hacia, J.G. 2001. Genome of the apes. Trends Genet. 17: 637-645.[CrossRef][Medline]
Hacia, J.G., Makalowski, W., Edgemon, K., Erdos, M.R., Robbins, C.M., Fodor, S.P., Brody, L.C., and Collins, F.S. 1998. Evolutionary sequence comparisons using high-density oligonucleotide arrays. Nat. Genet. 18: 155-158.[CrossRef][Medline]
Hacia, J.G., Fan, J.B., Ryder, O., Jin, L., Edgemon, K., Ghandour, G., Mayer, R.A., Sun, B., Hsie, L., Robbins, C.M., et al. 1999. Determination of ancestral alleles for human single-nucleotide polymorphisms using high-density oligonucleotide arrays. Nat. Genet. 22: 119-120.[CrossRef][Medline]
Hattori, M., Fujiyama, A., Taylor, T.D., Watanabe, H., Yada, T., Park, H.S., Toyoda, A., Ishii, K., Totoki, Y., and Choi, D.K. 2000. The DNA sequence of human chromosome 21. Nature 405: 311-319.[CrossRef][Medline]
Isshiki, S., Togayachi, A., Kudo, T., Nishihara, S., Watanabe, M., Kubota, T., Kitajima, M., Shiraishi, N., Sasaki, K., Andoh, T., et al. 1999. Cloning, expression, and characterization of a novel UDP-galactose:-N-acetylglucosamine 1,3-galactosyltransferase (3Gal-T5) responsible for synthesis of type 1 chain in colorectal and pancreatic epithelia and tumor cells derived therefrom. J. Biol. Chem. 274: 12499-12507.[Abstract/Free Full Text]
King, M.C. and Wilson, A.C. 1975. Evolution at two levels in humans and chimpanzees. Science 188: 107-116.[Free Full Text]
Koop, B.F., Tagle, D.A., Goodman, M., and Slightom, J.L. 1989. A molecular view of primate phylogeny and important systematic and evolutionary questions. Mol. Biol. Evol. 6: 580-612.[Abstract]
Nickerson, E. and Nelson, D.L. 1998. Molecular definition of pericentric inversion breakpoints occurring during the evolution of humans and chimpanzees. Genomics 50: 368-372.[CrossRef][Medline]
Patil, N., Berno, A.J., Hinds, D.A., Barrett, W.A., Doshi, J.M., Hacker, C.R., Kautzer, C.R., Lee, D.H., Marjoribanks, C., McDonough, D.P., et al. 2001. Blocks of limited haplotype diversity revealed by high-resolution scanning of human chromosome 21. Science 294: 1719-1723.[Abstract/Free Full Text]
Ueda, S., Washio, K., and Kurosaki, K. 1990. Human-specific sequences: Isolation of species-specific DNA regions by genome subtraction. Genomics 8: 7-12.[CrossRef][Medline]
Yunis, J.J. and Prakash, O. 1982. The origin of man: A chromosomal pictorial legacy. Science 215: 1525-1530.[Abstract/Free Full Text]
Received June 24, 2002;
accepted in revised format November 25, 2002.
13:341-346 © by 2003 Cold Spring Harbor Laboratory Press ISSN 1088-9051/03 $5.00
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ABSTRACT
RESULTS AND DISCUSSION
