Polymorphisms on SSC15q21-q26 Containing QTL for reproduction in Swine and its association with litter size.
ABSTRACT Several quantitative trait loci (QTL) for important reproductive traits (ovulation rate) have been identified on the porcine chromosome 15 (SSC15). To assist in the selection of positional candidate swine genes for these QTL on SSC15, twenty-one genes had already been assigned to SSC15 in a previous study in our lab, by using the radiation hybrid panel IMpRH. Further polymorphism studies were carried out on these positional candidate genes with four breeds of pigs (Duroc, Erhualian, Dahuabai and Landrace) harboring significant differences in reproduction traits. A total of nineteen polymorphisms were found in 21 genes. Among these, seven in six genes were used for association studies, whereby NRP2 polymorphism was found to be significantly (p < 0.05) associated with litter-size traits. NRP2 might be a candidate gene for pig-litter size based on its chromosome location (Du et al., 2006), significant association with litter-size traits and relationships with Sema and the VEGF super families.
- SourceAvailable from: pnas.org[show abstract] [hide abstract]
ABSTRACT: We previously reported a genomewide linkage study for human longevity using 308 long-lived individuals (LLI) (centenarians or near-centenarians) in 137 sibships and identified statistically significant linkage within chromosome 4 near microsatellite D4S1564. This interval spans 12 million bp and contains approximately 50 putative genes. To identify the specific gene and gene variants impacting lifespan, we performed a haplotype-based fine-mapping study of the interval. The resulting genetic association study identified a haplotype marker within microsomal transfer protein as a modifier of human lifespan. This same variant was tested in a second cohort of LLI from France, and although the association was not replicated, there was evidence for statistical distortion in the form of Hardy-Weinberg disequilibrium. Microsomal transfer protein has been identified as the rate-limiting step in lipoprotein synthesis and may affect longevity by subtly modulating this pathway. This study provides proof of concept for the feasibility of using the genomes of LLI to identify genes impacting longevity.Proceedings of the National Academy of Sciences 12/2003; 100(24):14115-20. · 9.74 Impact Factor
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ABSTRACT: Neuropilin is a type 1 membrane protein, which is highly conserved among Xenopus frog, chicken and mouse. The extracellular part of the neuropilin protein is composed of three unique domains, each of which is thought to be involved in molecular and/or cellular interactions. In mice, neuropilin is expressed in the cardiovascular system, nervous system and limbs at particular developmental stages. To clarify the roles of neuropilin in morphogenesis in vivo, we generated mouse embryonic stem (ES) cell clones that constitutively expressed exogenous neuropilin, then produced chimeras using these ES cell clones. The chimeras overexpressed neuropilin and were embryonic lethal. The chimeric embryos exhibited several morphological abnormalities; excess capillaries and blood vessels, dilation of blood vessels, malformed hearts, ectopic sprouting and defasciculation of nerve fibers, and extra digits. All of these abnormalities occurred in the organs in which neuropilin is expressed in normal development. The variety of abnormalities occurring in these chimeric embryos suggested diverse functions of neuropilin in embryonic morphogenesis, which may be ascribed to multiple interaction domains identified in the molecule. Correct spatiotemporal expression of neuropilin seems to be essential for normal development of the cardiovascular system, nervous system and limbs.Development 01/1996; 121(12):4309-18. · 6.21 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: Research over the last few years has revealed significant haplotype structure in the human genome. The characterization of these patterns, particularly in the context of medical genetic association studies, is becoming a routine research activity. Haploview is a software package that provides computation of linkage disequilibrium statistics and population haplotype patterns from primary genotype data in a visually appealing and interactive interface. AVAILABILITY: http://www.broad.mit.edu/mpg/haploview/ CONTACT: firstname.lastname@example.orgBioinformatics 02/2005; 21(2):263-5. · 5.32 Impact Factor
Polymorphisms on SSC15q21-q26 Containing QTL for reproduction in
Swine and its association with litter size
Hongli Du1, Jing Chen2, Jianxun Cui2, Xiaoning Wang1and Xiquan Zhang2
1School of Bioscience and Bioengineering, South China University of Technology, Guangzhou, China.
2College of Animal Science, South China Agricultural University, Guangzhou, China.
Several quantitative trait loci (QTL) for important reproductive traits (ovulation rate) have been identified on the por-
cine chromosome 15 (SSC15). To assist in the selection of positional candidate swine genes for these QTL on
SSC15, twenty-one genes had already been assigned to SSC15 in a previous study in our lab, by using the radiation
hybrid panel IMpRH. Further polymorphism studies were carried out on these positional candidate genes with four
breeds of pigs (Duroc, Erhualian, Dahuabai and Landrace) harboring significant differences in reproduction traits. A
total of nineteen polymorphisms were found in 21 genes. Among these, seven in six genes were used for association
studies, whereby NRP2 polymorphism was found to be significantly (p < 0.05) associated with litter-size traits. NRP2
might be a candidate gene for pig-litter size based on its chromosome location (Du et al., 2006), significant associa-
tion with litter-size traits and relationships with Sema and the VEGF super families.
Key words: porcine, reproductive traits, NRP2, candidate gene.
Received: January 14, 2008; Accepted: July 23, 2008.
More than 1800 quantitative trait loci (QTL) had al-
ready been mapped on the entire pig genome until June 3rd,
traits by developing a detailed comparative map and a SNP
map that would both constitute an effective method for as-
sisting in the selection of the underlying genes responsible
for the mapped QTL. For example, a QTL affecting meat
quality in chromosome 2p has already been well described
(Andersson-Eklund et al. 1998; Knott et al. 1998; de Ko-
ning et al. 1999), these methods being essential in the iden-
tification of regulatory mutation in the causal gene IGF-2
(Jeon et al. 1999; Nezer et al. 1999; de Koning et al. 2000;
Nezer et al. 2003; Van Laere et al. 2003).
Single nucleotide polymorphisms (SNP) are far more
abundant, with the occurrence of about one SNP per
1000 bp in human beings (Wang et al. 1998) and one SNP
per 200 bp in chickens (International Chicken Polymor-
phism Map Consortium, 2004), and are more amenable to
gies. Furthermore, SNP are extremely stable, occurring at a
rate of only one mutation in 2 x 108nucleotides in humans
(Sachidanandam et al. 2001). A straightforward strategy
for the identification of SNP is locus-specific amplification
(LSA) and comparative re-sequencing from multiple indi-
linkage disequilibrium (LD) and common haplotype pat-
becoming increasingly widespread since it has become
clear (Rioux et al. 2001; Van Eerdewegh et al. 2002;
Geesaman et al. 2003; Stoll et al. 2004) that intelligent use
of this information has the potential of making them much
role in the fine mapping of QTL and in proposed ge-
nome-wide association studies (Nezer et al. 2003).
porcine chromosome 15q21-q26 (Rathje et al. 1997;
which corresponds to chromosomal fragments containing
hundreds of genes. In a previous study in our lab,
twenty-one genes were assigned to SSC15 by using the ra-
diation hybrid panel IMpRH (Du et al, 2006). The goal of
the present study was to screen SNP in these genes and in-
vestigate their association with litter size for identifying
candidate genes in this QTL region. Seven polymorphisms
were chosen for investigating their effects on litter size by
using animals (unrelated individuals) which had already
been recorded for litter-size traits.
Materials and Methods
Ear samples from 237 domestic pigs from the four
breeds, Duroc, Erhualian, Dahuabai and Landrace, num-
Genetics and Molecular Biology, 32, 1, 69-74 (2009)
Copyright © 2009, Sociedade Brasileira de Genética. Printed in Brazil
Send correspondence to Xiquan Zhang. College of Animal Sci-
ence, South China Agricultural University, Wushan Street,
Guangzhou 510642, China. E-mail: email@example.com.
bering 38, 58, 61 and 80 individuals, respectively, were
Co. Ltd. (Guangdong, China), Guangdong Changjiang
Foodstuff Company Ltd. (Guangdong, China) and Guang-
dong Banling Pig Farm (Guangdong, China). One hundred
and fifty eight individuals were recorded as originating 4 or
more than 4 litters. A fertility index was calculated individu-
ally by litter size, prenatal survival and litter-weight for all
the litters of the 158 animals and assigned to three parame-
ters: litter size (LS), prenatal survival (PS), litter-weight
Genomic DNA pool preparation
Porcine genomic DNA was extracted from ear sam-
ples using the Nucleon kit (TaKaRa, Japan). DNA concen-
trations were determined by O.D. measurements, using a
Biophotometer (Eppendorf, Germany). All samples were
diluted to a concentration of 20 ng/?L. The breed DNA
pool was constructed by mixing 30 samples from each
breed at equal volume, whereby four breed DNA pools
PCR and sequencing
The 21 primer pairs (Table 1) were also used to am-
plify genomic DNA fragments with the four breed DNA
pools described above. Direct sequencing of these PCR
products was performed using an ABI 377 automatic se-
quencer (Applied Biosystems, Foster City, Calif., USA)
following standard protocols. The sequence for each single
gene was subjected to a BLAST search to confirm both its
origin and ortholog status.
PCR reactions were performed in a final volume of
25 ?L containing 50 ng of porcine genomic DNA, 0.4 ?M
Taq buffer, and 0.7 U of Taq polymerase (TaKaRa, Tokyo,
Japan.). PCR conditions were as follows: 94 °C for 5 min
sion at 72 °C. PCR products were then examined by elec-
trophoresis on a 2% agarose gel stained with ethidium
bromide and then photographed.
Polymorphism identification and selection
Sequencing gel images obtained from previous ex-
periments were analyzed using Sequencing Analysis soft-
ware (Applied Biosystems, Foster City, Calif., USA) for
lane tracking and trace file extraction. Subsequently, all
trace files were analyzed using the Pregap4 program of the
Staden software package (Bonfield and Staden 1996;
http://www.mrc-lmb.cam.ac.uk/pubseq). All nucleotide
positions at which disagreement occurred were tagged as
putative polymorphism positions. Sequences were submit-
ted to the GenBank. Polymorphisms identified in the se-
70Du et al.
Table 1 - Information for PCR amplification of the genes genotyped on the IMpRH panel.
Gene namePrimers (forward/ reverse) Tm (°C)Porcine sequence Acc. n. Length (bp)
61 AY805669 553/552
quences are represented by the IUB ambiguity codes
reflecting alleles found in the DNA pools.
In addition, the preliminary allele distribution of each
polymorphism in each breed could be estimated based on
peak heights at the polymorphic site in trace files (Cui et al.
be deduced to some extent, due to the diverse allelic distribu-
tion in different breeds. According to this principle, the seven
polymorphisms identified in six genes (DPP4, SH3BP4,
ORC2L, NRP2, COL4A4 and TRTP12) were selected and
genotyped by the PCR-RFLP method, their effects on litter
the trait of litter size had already been recorded.
Genotyping, haplotype construction and allelic
Erhualian, Dahuabai and Landrace, numbering 38, 58, 61
and 80 individuals, respectively, were genotyped by the
PCR-RFLP method at the seven polymorphism sites, se-
lected as above. Fragments of DPP4, SH3BP4, ORC2L,
NRP2, and TRTP12 were digested by the CfrI, XapI,
BseMI, Eco105I and Bsh1236I endonucleases, respec-
tively, and the COL4A4 fragment by the TasI and NdeI
endonucleases, to be then electrophoresed on 3% agarose
gel for genotyping. The allelic frequencies of the seven
polymorphisms were calculated in all the populations.
Haplotypes were constructed with two SNP for
COL4A4 in all experimental animals, through applying the
PHASE programme (Stephens et al. 2001), with the recon-
struction of haplotypes from population data as the main
Linkage disequilibrium analyses
In this study, LD analyses were performed using
HAPLOVIEW software (Barrett et al. 2005) in a popula-
tion of 237 individuals, and LD measured with a parameter
of r2(Ardlie et al. 2002).
Marker-trait association analysis
The association of single polymorphism or haplotype
with litter size was analyzed by means of the GLM proce-
Cary, NC, USA). The model included parity, genotype (or
haplotype), farm and breed as fixed effects for all the 158
animals. In addition, an association study was also carried
out for each breed. Values were considered significant at
p < 0.05 and presented as least square means (LSM) ? stan-
dard error means (SEM).
Direct sequencing of the 21 gene PCR products in
both directions yielded reliable and readable sequences for
pooled DNA samples from Duroc, Erhualian, Dahuabai
and Landrace pigs.
Direct sequencing of the 21 gene PCR products in
both directions yielded 168 readings, all of which being as-
sembled in 21 distinct contigs for the four pooled DNA
samples. Contigs varied in length between 220 and 748 bp,
with an average of 429 bp, and a total length of 8 943 bp.
The assembled sequences were submitted to GenBank, and
accepted with the uninterrupted accession numbers from
AY805665 to AY805748 (Table 1). At least one polymor-
phism was identified in 11 genes (COL4A4, DPP4,
SP3 and TRIP12) among the 21 genes analyzed. We identi-
943 bp, corresponding to an overall average of one poly-
cated in the SSC15 q23-q25 region. Detailed information
on each polymorphism is available in the submitted se-
Genotypes, haplotypes and their frequencies
Three haplotypes were found at each site of six genes
(DPP4, SH3BP4, ORC2L, NRP2, COL4A4 and TRTP12).
Large breed differences were observed in the allelic fre-
quencies of 6 SNPs and 4-bp indel (Table 2). The most sig-
nificant differences were found between the Duroc and
Erhualian breeds at the T-SH3BP4-G, T-NRP2-C and C-
Haplotypes constructed based on two SNPs of the
COL4A4 gene and their frequencies in four populations,
are shown in Table 3. Four haplotypes were identified in
237 individuals, in which the three most abundant, desig-
of frequency. Haplotype H4 (T T) seems to correspond to a
recombination between H1 and H3 and is present only in
Duroc pigs. Their frequencies are significantly different
among the four breeds.
LD and marker-trait association
The r2value was estimated for each of two polymor-
phic sites, the highest r2value (0.59) being obtained be-
loci forming a haplotype block.
The effect of single polymorphism or haplotype on
reproduction traits in pigs was estimated simultaneously
for the parameters of LS, PS and LW. We found that NRP2
genotypes had a significant effect on litter-size traits (type
for PS; type III F = 9.17, p = 0.0001 for LW), whereas all
the other genotypes at any other polymorphism site had no
fect of NRP2 genotypes can also be inferred by association
analysis which was carried out for Dahubai and Landrace
Functional gene research in pigs71
individuals, with the SAS GLM procedure including parity
and genotype (or haplotype) as fixed effects (Table 4).
In our previous study (Du et al., 2006), all the genes
the QTL regions at 53-101 cM, and 79.3-102.5 cM charac-
terized for the ovulation rate (Pig QTL Database, QTL on
Pig Chromosome 15). Therein, KLF7, NRP2 and ORC2L
were located very close to the QTL center position (79 cM)
(Rohrer et al. 1999), as the adjacent microsatellites
SW1316, SWR1002 and SW2083 were mapped at
73.1 cM, 76 cM and 81.1 cM, respectively, on the MARC
larly, EPHA4, COL4A4 and TRIP12 were located near to
the QTL center position (88.5 cM) (Rathje et al. 1997), de-
duced from the position of SW936, SW906 and SW2608
mapped at 88.5 cM, 89.3 cM and 95 cM respectively on the
MARC genetic map. Therefore, these six genes are the
most possible positional candidate genes among the 21
Erhualian is one of the Taihu breeds with the highest
fertility, producing around 16 piglets all told and 14 live
piglets on an average per litter. Dahuabai is a native Chi-
nese breed which produces about 14 piglets overall and 13
breeds with a rapid growth rate, but producing far fewer
piglets per litter than native Chinese breeds do. The four
breeds were investigated to screen for potential polymor-
phisms related to reproductive traits in SSC15 based on
ter sizes. Seven polymorphisms in the six genes DPP4,
SH3BP4, ORC2L, NRP2, COL4A4 and TRTP12 were se-
marker-trait association studies, based on approximate al-
lele distribution in the four breeds. Allelic frequency stud-
ies revealed that the frequencies of T-SH3BP4, T-NRP2
and C-COL4A4-2 varied significantly among the four
breeds, the most significant differences being found espe-
cially between the Duroc and Erhualian breeds at the three
sites. However, only the significant association of T-
NRP2-C with litter size traits (type III F = 5.18, p = 0.0059
for LS; type III F = 5.70, p = 0.0035 for PS; type III
sociation studies were carried out on each polymorphism
(Table 4). The over dominance expressions of T-NRP2-C
for the PS trait are also to be found in Table 4. The signifi-
be observed in the Landrace and Dahuabai breeds, which
can validate the results for all the animals to some extent.
72Du et al.
Table 2 - Allele frequencies of the 7 polymorphic sites in 4 pig populations and Pearson’s ?2value.
Breeds (n. pig)a
DPP4-1 SH3BP4ORC2LNRP2COL4A4-2COL4A4-3 TRTP12
Duroc (38)01.00010 1.0001.000.46 0.540.51 0.490.46 0.54
Erhualian (58) 0.290.71 1.000 0.35 0.65 0.700.30 1.000 0.210.790.59 0.41
Dahuabai (61)0.52 0.480.960.04 0.700.300.660.340.930.070.530.47 0.280.72
Landrace (80)0.04 0.96 0.140.8601.00 0.040.96 0.760.240.310.690.130.87
105.77234.41 186.33203.80103.3557.80 66.04
AY805665AY805697 AY805717 AY805721AY805733 AY805733AY805741
Variation positionPos 296Pos 242 Pos 187Pos 62 Pos 147Pos 188 Pos 69
aThe number in brackets is the individual number investigated in each breed.
6> 16.81, p < 0.01.
cPorcine sequence accession numbers.
Table 3 - Base constitutions of COL4A4 haplotypes and their frequencies.
COL4A4-2 COL4A4-3Duroc(38)Erhualian(58) Dahuabai (61) Landrace (80)
h3TA 0.460 0.070.24
h4 TT 0.08000
aThe number in brackets is the individual number investigated in each breed.
The association of NRP2 with litter-size traits is con-
tion rate (Rohrer et al. 1999), since the latter is a major
factor for litter size. Neuropilin (NRP, previously referred
to as A5) is a type I transmembrane protein which is widely
distributed in vertebrate species such as Xenopus, chickens
and mice (Fujisawa et al. 1995). The extracellular part of
the neuropilin protein is composed of three unique do-
and/or cellular interactions (Kitsukawa et al. 1995). NRP2
selectively to mediate repulsive guidance events in discrete
populations of neurons (Chen et al. 1997). It has also been
found to be a receptor for the vascular endothelial growth
factor (VEGF) forms VEGF-145 and VEGF-165 and for
additional VEGF family-members, such as the placenta
growth factor (PlGF-2) (Gluzman-Poltorak et al. 2000;
Neufeld et al. 2002). VEGF induces endothelial cell prolif-
eration, promotes cell migration and inhibits apoptosis. A
recent study has revealed that NRP2 is probably related to
lymphangiogenic growth (Lohela et al. 2003) and a defi-
ciency in NRP2 suppresses VEGF-induced retinal neo-
be considered as a candidate gene for litter-size traits based
on its chromosome location, significant association with
litter-size traits and relationships with the Sema and VEGF
This work was funded by projects under the Major
State Basic Research Development Program, China, pro-
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Associate Editor: Pedro Franklin Barbosa
License information: This is an open-access article distributed under the terms of the
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74Du et al.