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1.
The regular decrease of female fertility over time is a major concern in modern dairy cattle industry. Only half of this decrease is explained by indirect response to selection on milk production, suggesting the existence of other factors such as embryonic lethal genetic defects. Genomic regions harboring recessive deleterious mutations were detected in three dairy cattle breeds by identifying frequent haplotypes (>1%) showing a deficit in homozygotes among Illumina Bovine 50k Beadchip haplotyping data from the French genomic selection database (47,878 Holstein, 16,833 Montbéliarde, and 11,466 Normande animals). Thirty-four candidate haplotypes (p<10−4) including previously reported regions associated with Brachyspina, CVM, HH1, and HH3 in Holstein breed were identified. Haplotype length varied from 1 to 4.8 Mb and frequencies from 1.7 up to 9%. A significant negative effect on calving rate, consistent in heifers and in lactating cows, was observed for 9 of these haplotypes in matings between carrier bulls and daughters of carrier sires, confirming their association with embryonic lethal mutations. Eight regions were further investigated using whole genome sequencing data from heterozygous bull carriers and control animals (45 animals in total). Six strong candidate causative mutations including polymorphisms previously reported in FANCI (Brachyspina), SLC35A3 (CVM), APAF1 (HH1) and three novel mutations with very damaging effect on the protein structure, according to SIFT and Polyphen-2, were detected in GART, SHBG and SLC37A2 genes. In conclusion, this study reveals a yet hidden consequence of the important inbreeding rate observed in intensively selected and specialized cattle breeds. Counter-selection of these mutations and management of matings will have positive consequences on female fertility in dairy cattle.  相似文献   

2.
Using genomic data, lethal recessives may be discovered from haplotypes that are common in the population but never occur in the homozygote state in live animals. This approach only requires genotype data from phenotypically normal (i.e. live) individuals and not from the affected embryos that die. A total of 7,937 Nordic Holstein animals were genotyped with BovineSNP50 BeadChip and haplotypes including 25 consecutive markers were constructed and tested for absence of homozygotes states. We have identified 17 homozygote deficient haplotypes which could be loosely clustered into eight genomic regions harboring possible recessive lethal alleles. Effects of the identified haplotypes were estimated on two fertility traits: non-return rates and calving interval. Out of the eight identified genomic regions, six regions were confirmed as having an effect on fertility. The information can be used to avoid carrier-by-carrier mattings in practical animal breeding. Further, identification of causative genes/polymorphisms responsible for lethal effects will lead to accurate testing of the individuals carrying a lethal allele.  相似文献   

3.
Bovine mastitis is a very complex and common disease of dairy cattle and a major source of economic losses to the dairy industry worldwide. In this study, the bovine TLR4 was taken as a candidate gene for mastitis resistance. This study aimed to analyze the associations of single nucleotide polymorphisms (SNP) or haplotype and somatic cell score (SCS) in 404 Chinese commercial dairy cattle including Chinese Holstein, Sanhe cattle and Chinese Simmental breeds. The polymerase chain reaction and sequencing methods were used for detecting genotype and allele frequency distribution of the two SNPs (rs8193062, rs8193064), statistical results showed that T allele at rs8193062 and C allele at rs8193064 were the predominate alleles. Moreover, six SNPs, including two SNPs (rs8193062, rs8193064) and four SNPs (rs8193060, rs8193069, rs29017188, rs8193046) which were chosen according the polymorphism level for the same cattle populations in previous studies, were used for haplotype analysis, the results revealed that twenty-one haplotypes were found in the mentioned animals, of which, Hap1 (30.5 %) and Hap2 (30.4 %) were the most common haplotypes. Hap2, Hap4 and Hap12 might negatively effect on milk SCS, whereas Hap13 might positively effect on milk SCS. The results in this study might assist in marker assisted selection and provided some reference to be implemented in breeding programs to improve the mastitis resistance of dairy cattle.  相似文献   

4.
Fertility is one of the most important traits in dairy cattle, and has been steadily declining over the last decades. We herein use state-of-the-art genomic tools, including high-throughput SNP genotyping and next-generation sequencing, to identify a 3.3 Kb deletion in the FANCI gene causing the brachyspina syndrome (BS), a rare recessive genetic defect in Holstein dairy cattle. We determine that despite the very low incidence of BS (<1/100,000), carrier frequency is as high as 7.4% in the Holstein breed. We demonstrate that this apparent discrepancy is likely due to the fact that a large proportion of homozygous mutant calves die during pregnancy. We postulate that several other embryonic lethals may segregate in livestock and significantly compromise fertility, and propose a genotype-driven screening strategy to detect the corresponding deleterious mutations.  相似文献   

5.
BackgroundWith the availability of massive SNP data for several economically important cattle breeds, haplotype tests have been performed to identify unknown recessive disorders. A number of so-called lethal haplotypes, have been uncovered in Holstein Friesian cattle and, for at least seven of these, the causative mutations have been identified in candidate genes. However, several lethal haplotypes still remain elusive. Here we report the molecular genetic causes of lethal haplotype 5 (HH5) and cholesterol deficiency (CDH). A targeted enrichment for the known genomic regions, followed by massive parallel sequencing was used to interrogate for causative mutations in a case/control approach.MethodsTargeted enrichment for the known genomic regions, followed by massive parallel sequencing was used in a case/control approach. PCRs for the causing mutations were developed and compared to routine imputing in 2,100 (HH5) and 3,100 (CDH) cattle.ResultsHH5 is caused by a deletion of 138kbp, spanning position 93,233kb to 93,371kb on chromosome 9 (BTA9), harboring only dimethyl-adenosine transferase 1 (TFB1M). The deletion breakpoints are flanked by bovine long interspersed nuclear elements Bov-B (upstream) and L1ME3 (downstream), suggesting a homologous recombination/deletion event. TFB1M di-methylates adenine residues in the hairpin loop at the 3’-end of mitochondrial 12S rRNA, being essential for synthesis and function of the small ribosomal subunit of mitochondria. Homozygous TFB1M-/- mice reportedly exhibit embryonal lethality with developmental defects. A 2.8% allelic frequency was determined for the German HF population. CDH results from a 1.3kbp insertion of an endogenous retrovirus (ERV2-1-LTR_BT) into exon 5 of the APOB gene at BTA11:77,959kb. The insertion is flanked by 6bp target site duplications as described for insertions mediated by retroviral integrases. A premature stop codon in the open reading frame of APOB is generated, resulting in a truncation of the protein to a length of only <140 amino acids. Such early truncations have been shown to cause an inability of chylomicron excretion from intestinal cells, resulting in malabsorption of cholesterol. The allelic frequency of this mutation in the German HF population was 6.7%, which is substantially higher than reported so far. Compared to PCR assays inferring the genetic variants directly, the routine imputing used so far showed a diagnostic sensitivity of as low as 91% (HH5) and 88% (CDH), with a high specificity for both (≥99.7%).ConclusionWith the availability of direct genetic tests it will now be possible to more effectively reduce the carrier frequency and ultimately eliminate the disorders from the HF populations. Beside this, the fact that repetitive genomic elements (RE) are involved in both diseases, underline the evolutionary importance of RE, which can be detrimental as here, but also advantageous over generations.  相似文献   

6.
7.
Clinical mastitis (CM) is an inflammatory disease occurring in the mammary glands of lactating cows. CM is under genetic control, and a prominent CM resistance QTL located on chromosome 6 was reported in various dairy cattle breeds. Nevertheless, the biological mechanism underpinning this QTL has been lacking. Herein, we mapped, fine-mapped, and discovered the putative causal variant underlying this CM resistance QTL in the Dutch dairy cattle population. We identified a ~12 kb multi-allelic copy number variant (CNV), that is in perfect linkage disequilibrium with a lead SNP, as a promising candidate variant. By implementing a fine-mapping and through expression QTL mapping, we showed that the group-specific component gene (GC), a gene encoding a vitamin D binding protein, is an excellent candidate causal gene for the QTL. The multiplicated alleles are associated with increased GC expression and low CM resistance. Ample evidence from functional genomics data supports the presence of an enhancer within this CNV, which would exert cis-regulatory effect on GC. We observed that strong positive selection swept the region near the CNV, and haplotypes associated with the multiplicated allele were strongly selected for. Moreover, the multiplicated allele showed pleiotropic effects for increased milk yield and reduced fertility, hinting that a shared underlying biology for these effects may revolve around the vitamin D pathway. These findings together suggest a putative causal variant of a CM resistance QTL, where a cis-regulatory element located within a CNV can alter gene expression and affect multiple economically important traits.  相似文献   

8.

Background

The absence of horns, called polled phenotype, is the favored trait in modern cattle husbandry. To date, polled cattle are obtained primarily by dehorning calves. Dehorning is a practice that raises animal welfare issues, which can be addressed by selecting for genetically hornless cattle. In the past 20 years, there have been many studies worldwide to identify unique genetic markers in complete association with the polled trait in cattle and recently, two different alleles at the POLLED locus, both resulting in the absence of horns, were reported: (1) the Celtic allele, which is responsible for the polled phenotype in most breeds and for which a single candidate mutation was detected and (2) the Friesian allele, which is responsible for the polled phenotype predominantly in the Holstein-Friesian breed and in a few other breeds, but for which five candidate mutations were identified in a 260-kb haplotype. Further studies based on genome-wide sequencing and high-density SNP (single nucleotide polymorphism) genotyping confirmed the existence of the Celtic and Friesian variants and narrowed down the causal Friesian haplotype to an interval of 145 kb.

Results

Almost 6000 animals were genetically tested for the polled trait and we detected a recombinant animal which enabled us to reduce the Friesian POLLED haplotype to a single causal mutation, namely a 80-kb duplication. Moreover, our results clearly disagree with the recently reported perfect co-segregation of the POLLED mutation and a SNP at position 1 390 292 bp on bovine chromosome 1 in the Holstein-Friesian population.

Conclusion

We conclude that the 80-kb duplication, as the only remaining variant within the shortened Friesian haplotype, represents the most likely causal mutation for the polled phenotype of Friesian origin.  相似文献   

9.
Bovine Progressive Degenerative Myeloencephalopathy (Weaver Syndrome) is a recessive neurological disease that has been observed in the Brown Swiss cattle breed since the 1970’s in North America and Europe. Bilateral hind leg weakness and ataxia appear in afflicted animals at 6 to 18 months of age, and slowly progresses to total loss of hind limb control by 3 to 4 years of age. While Weaver has previously been mapped to Bos taurus autosome (BTA) 4∶46–56 Mb and a diagnostic test based on the 6 microsatellite (MS) markers is commercially available, neither the causative gene nor mutation has been identified; therefore misdiagnosis can occur due to recombination between the diagnostic MS markers and the causative mutation. Analysis of 34,980 BTA 4 SNPs genotypes derived from the Illumina BovineHD assay for 20 Brown Swiss Weaver carriers and 49 homozygous normal bulls refined the Weaver locus to 48–53 Mb. Genotyping of 153 SNPs, identified from whole genome sequencing of 10 normal and 10 carrier animals, across a validation set of 841 animals resulted in the identification of 41 diagnostic SNPs that were concordant with the disease. Except for one intergenic SNP all are associated with genes expressed in nervous tissues: 37 distal to NRCAM, one non-synonymous (serine to asparagine) in PNPLA8, one synonymous and one non-synonymous (lysine to glutamic acid) in CTTNBP2. Haplotype and imputation analyses of 7,458 Brown Swiss animals with Illumina BovineSNP50 data and the 41 diagnostic SNPs resulted in the identification of only one haplotype concordant with the Weaver phenotype. Use of this haplotype and the diagnostic SNPs more accurately identifies Weaver carriers in both Brown Swiss purebred and influenced herds.  相似文献   

10.
Lactoferrin (Lf) is naturally produced by the mammary gland, having biological functions of antibacterial and anti-inflammatory activities. To investigate whether the Lf gene is associated with mastitis in dairy cattle, a DNA sequencing approach was used to identify single nucleotide polymorphisms (SNPs) in the gene. Three previously reported SNPs in the 5′ flanking region and one novel SNP in exon1 of Lf gene were identified. A total of 353 individuals from Holstein cattle populations were genotyped for their SNPs using Created Restriction Site PCR (CRS-PCR) and PCR-RFLP methods. Twenty-two and nineteen combinations of three SNPs (g.3440T>G, g.3879_3880insG, and g.4432T>C) and another three SNPs (g.3429G>A, g.3440T>G, g.3879_3880insG) were observed, respectively. The result of haplotype analysis of four SNPs showed that fourteen different haplotypes were identified. Two major haplotypes (GECB and GECA) occurred with a frequency of 22.5 and 18.5% in the study population, respectively. Statistical analyses revealed no significant association between one single SNP of Lf gene and SCS, whereas significant associations between their combined genotypes of three SNPs, haplotype and SCS. Combined genotype EFCDBB and GGEFDD with the lowest SCS were favorable for the mastitis resistance. They may be used as a possible candidate for marker-assisted selection in dairy cattle breeding program.  相似文献   

11.

Background

Cattle breeding populations are susceptible to the propagation of recessive diseases. Individual sires generate tens of thousands of progeny via artificial insemination. The frequency of deleterious alleles carried by such sires may increase considerably within few generations. Deleterious alleles manifest themselves often by missing homozygosity resulting from embryonic/fetal, perinatal or juvenile lethality of homozygotes.

Results

A scan for homozygous haplotype deficiency in 25,544 Fleckvieh cattle uncovered four haplotypes affecting reproductive and rearing success. Exploiting whole-genome resequencing data from 263 animals facilitated to pinpoint putatively causal mutations in two of these haplotypes. A mutation causing an evolutionarily unlikely substitution in SUGT1 was perfectly associated with a haplotype compromising insemination success. The mutation was not found in homozygous state in 10,363 animals (P = 1.79 × 10−5) and is thus likely to cause lethality of homozygous embryos. A frameshift mutation in SLC2A2 encoding glucose transporter 2 (GLUT2) compromises calf survival. The mutation leads to premature termination of translation and activates cryptic splice sites resulting in multiple exon variants also with premature translation termination. The affected calves exhibit stunted growth, resembling the phenotypic appearance of Fanconi-Bickel syndrome in humans (OMIM 227810), which is also caused by mutations in SLC2A2.

Conclusions

Exploiting comprehensive genotype and sequence data enabled us to reveal two deleterious alleles in SLC2A2 and SUGT1 that compromise pre- and postnatal survival in homozygous state. Our results provide the basis for genome-assisted approaches to avoiding inadvertent carrier matings and to improving reproductive and rearing success in Fleckvieh cattle.

Electronic supplementary material

The online version of this article (doi:10.1186/s12864-015-1483-7) contains supplementary material, which is available to authorized users.  相似文献   

12.
Linkage disequilibrium in the North American Holstein population   总被引:2,自引:0,他引:2  
Linkage disequilibrium was estimated using 7119 single nucleotide polymorphism markers across the genome and 200 animals from the North American Holstein cattle population. The analysis of maternally inherited haplotypes revealed strong linkage disequilibrium ( r 2   >   0.8) in genomic regions of ∼50 kb or less. While linkage disequilibrium decays as a function of genomic distance, genomic regions within genes showed greater linkage disequilibrium and greater variation in linkage disequilibrium compared with intergenic regions. Identification of haplotype blocks could characterize the most common haplotypes. Although maximum haplotype block size was over 1 Mb, mean block size was 26–113 kb by various definitions, which was larger than that observed in humans (∼10 kb). Effective population size of the dairy cattle population was estimated from linkage disequilibrium between single nucleotide polymorphism marker pairs in various haplotype ranges. Rapid reduction of effective population size of dairy cattle was inferred from linkage disequilibrium in recent generations. This result implies a loss of genetic diversity because of the high rate of inbreeding and high selection intensity in dairy cattle. The pattern observed in this study indicated linkage disequilibrium in the current dairy cattle population could be exploited to refine mapping resolution. Changes in effective population size during past generations imply a necessity of plans to maintain polymorphism in the Holstein population.  相似文献   

13.
In dairy cattle, the widespread use of artificial insemination has resulted in increased selection intensity, which has led to spectacular increase in productivity. However, cow fertility has concomitantly severely declined. It is generally assumed that this reduction is primarily due to the negative energy balance of high-producing cows at the peak of lactation. We herein describe the fine-mapping of a major fertility QTL in Nordic Red cattle, and identify a 660-kb deletion encompassing four genes as the causative variant. We show that the deletion is a recessive embryonically lethal mutation. This probably results from the loss of RNASEH2B, which is known to cause embryonic death in mice. Despite its dramatic effect on fertility, 13%, 23% and 32% of the animals carry the deletion in Danish, Swedish and Finnish Red Cattle, respectively. To explain this, we searched for favorable effects on other traits and found that the deletion has strong positive effects on milk yield. This study demonstrates that embryonic lethal mutations account for a non-negligible fraction of the decline in fertility of domestic cattle, and that associated positive effects on milk yield may account for part of the negative genetic correlation. Our study adds to the evidence that structural variants contribute to animal phenotypic variation, and that balancing selection might be more common in livestock species than previously appreciated.  相似文献   

14.
The service sire has been recognized as an important factor affecting herd fertility in dairy cattle. Recent studies suggest that genetic factors explain part of the difference in fertility among Holstein sires. The main objective of this study was to dissect the genetic architecture of sire fertility in US Jersey cattle. The dataset included 1.5 K Jersey bulls with sire conception rate (SCR) records and 96 K single nucleotide polymorphism (SNP) markers spanning the whole genome. The analysis included whole‐genome scans for both additive and non‐additive effects and subsequent functional enrichment analyses using KEGG Pathway, Gene Ontology (GO) and Medical Subject Headings (MeSH) databases. Ten genomic regions located on eight different chromosomes explained more than 0.5% of the additive genetic variance for SCR. These regions harbor genes, such as PKDREJ, EPB41L2, PDGFD, STX2, SLC25A20 and IP6K1, that are directly implicated in testis development and spermatogenesis, sperm motility and the acrosome reaction. In addition, the genomic scan for non‐additive effects identified two regions on BTA11 and BTA25 with marked recessive effects. These regions harbor three genes—FER1L5, CNNM4 and DNAH3—with known roles in sperm biology. Moreover, the gene‐set analysis revealed terms associated with calcium regulation and signaling, membrane fusion, sperm cell energy metabolism, GTPase activity and MAPK signaling. These gene sets are directly implicated in sperm physiology and male fertility. Overall, this integrative genomic study unravels genetic variants and pathways affecting Jersey bull fertility. These findings may contribute to the development of novel genomic strategies for improving sire fertility in Jersey cattle.  相似文献   

15.
Ticks and tick‐born diseases are major constraints on cattle production in tropical and subtropical regions in the world. Previously, we identified single nucleotide polymorphisms (SNPs) associated with tick resistance on bovine chromosome 3 at approximately 70 Mb. In this study, we genotyped a dairy (n = 1133) and a beef (n = 774) sample to confirm the association of the intronic SNP rs29019303 and its gene (ELTD1) with tick burden. We genotyped 18 additional SNPs in a region of 181 kb and found that rs29019303 was significantly (P < 0.05) associated with tick burden in both samples with the same favourable allele. A second SNP in this same genomic region was also significantly associated with tick burden in each sample. The associations using haplotypes were stronger than for single markers, including a haplotype of nine tag SNPs that was highly significantly (P = 0.0008) associated with tick counts in the dairy animals. This haplotype and two others were significant after Bonferroni correction for multiple testing. The estimated size of the effects was close to 0.9% of the residual variance in both samples tested.  相似文献   

16.
17.
Congenital myasthenic syndromes (CMSs) are heterogeneous neuromuscular disorders characterized by skeletal muscle weakness caused by disruption of signal transmission across the neuromuscular junction (NMJ). CMSs are rarely encountered in veterinary medicine, and causative mutations have only been identified in Old Danish Pointing Dogs and Brahman cattle to date. Herein, we characterize a novel CMS in 2 Labrador Retriever littermates with an early onset of marked generalized muscle weakness. Because the sire and dam share 2 recent common ancestors, CMS is likely the result of recessive alleles inherited identical by descent (IBD). Genome-wide SNP profiles generated from the Illumina HD array for 9 nuclear family members were used to determine genomic inheritance patterns in chromosomal regions encompassing 18 functional candidate genes. SNP haplotypes spanning 3 genes were consistent with autosomal recessive transmission, and microsatellite data showed that only the segment encompassing COLQ was inherited IBD. COLQ encodes the collagenous tail of acetylcholinesterase, the enzyme responsible for termination of signal transduction in the NMJ. Sequences from COLQ revealed a variant in exon 14 (c.1010T>C) that results in the substitution of a conserved amino acid (I337T) within the C-terminal domain. Both affected puppies were homozygous for this variant, and 16 relatives were heterozygous, while 288 unrelated Labrador Retrievers and 112 dogs of other breeds were wild-type. A recent study in which 2 human CMS patients were found to be homozygous for an identical COLQ mutation (c.1010T>C; I337T) provides further evidence that this mutation is pathogenic. This report describes the first COLQ mutation in canine CMS and demonstrates the utility of SNP profiles from nuclear family members for the identification of private mutations.  相似文献   

18.
Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a clinically homogeneous form of early-onset familial spastic ataxia with prominent myelinated retinal nerve fibers. More than 300 patients have been identified, and most of their families originated in the Charlevoix-Saguenay region of northeastern Quebec, where the carrier prevalence has been estimated to be 1/22. Consistent with the hypothesis of a founder effect, we observed excess shared homozygosity at 13q11, among patients in a genomewide scan of 12 families. Analysis of 19 pedigrees demonstrated very tight linkage between the ARSACS locus and an intragenic polymorphism of the gamma-sarcoglycan (SGCG) gene, but genomic DNA sequence analysis of all eight exons of SGCG revealed no disease-causing mutation. On the basis of haplotypes composed of seven marker loci that spanned 11.1 cM, the most likely position of the ARSACS locus was 0.42 cM distal to the SGCG polymorphism. Two groups of ARSACS-associated haplotypes were identified: a large group that carries a common SGCG allele and a small group that carries a rare SGCG allele. The haplotype groups do not appear to be closely related. Therefore, although chromosomes within each haplotype group may harbor a single ARSACS mutation identical by descent, the two mutations could have independent origins.  相似文献   

19.
Maple syrup urine disease (MSUD) is a rare, autosomal recessive disorder of branched-chain amino acid metabolism. We noted that a large proportion (10 of 34) of families with MSUD that were followed in our clinic were of Ashkenazi Jewish (AJ) descent, leading us to search for a common mutation within this group. On the basis of genotyping data suggestive of a conserved haplotype at tightly linked markers on chromosome 6q14, the BCKDHB gene encoding the E1beta subunit was sequenced. Three novel mutations were identified in seven unrelated AJ patients with MSUD. The locations of the affected residues in the crystal structure of the E1beta subunit suggested possible mechanisms for the deleterious effects of these mutations. Large-scale population screening of AJ individuals for R183P, the mutation present in six of seven patients, revealed that the carrier frequency of the mutant allele was approximately 1/113; the patient not carrying R183P had a previously described homozygous mutation in the gene encoding the E2 subunit. These findings suggested that a limited number of mutations might underlie MSUD in the AJ population, potentially facilitating prenatal diagnosis and carrier detection of MSUD in this group.  相似文献   

20.
We investigated the RGS4 as a susceptibility gene for schizophrenia in Chinese Han (184 trios and 138 sibling pairs, a total of 322 families) and Scottish (580 cases and 620 controls) populations using both a family trio and case-control design. Both the samples had statistical power greater than 70% to detect a heterozygote genotype relative risk of >1.2 for frequent RGS4-risk alleles. We genotyped four single nucleotide polymorphisms (SNPs) which have previously been associated with schizophrenia as either individually or part of haplotypes. Allele frequencies and linkage disequilibrium between the SNPs was similar in the two populations. In the Chinese sample, no individual SNPs or any of their haplotypes were associated with schizophrenia. In the Scottish population, one SNP (SNP7) was significantly over-represented in the cases compared with the controls (0.44 vs. 0.38; A allele; chi(2) 7.08, P = 0.011 after correction for correlation between markers by permutation testing). One two-marker haplotype, composed of alleles T and A of SNP4 and SNP7, respectively, showed individual significance after correction by permutation testing (chi(2) 6.8; P = 0.04). None of the full four-marker haplotypes showed association, including the G-G-G-G haplotype previously associated with schizophrenia in more than one sample and the A-T-A-A haplotype. Thus, our data do not directly replicate previous associations of RGS4, but association with SNP 7 in the Scottish population provides some support for a role in schizophrenia susceptibility. We cannot conclusively exclude RGS4, as associated haplotypes are likely to be surrogates for unknown causative alleles, whose relationship with overlying haplotypes may differ between the population groups. Differences in the association seen across the two populations could result from methodological factors such as diagnostic differences but most likely result from ethnic differences in haplotype structures within RGS4.  相似文献   

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