Breed Differences in Serum Testosterone Levels of Male Pigs Are Highly Correlated with Differences in Testicular mRNA Levels of Enzymes and Proteins Involved in Testosterone Biosynthesis Process.

To clarify the causes of breed differences in serum testosterone levels of male pigs, which affect the mRNA expression of drug metabolizing enzymes and drug transporters in the liver and kidney, we focused on testicular enzymes and proteins involved in testosterone biosynthesis process and comparatively examined their mRNA levels by real time RT-PCR among low serum testosterone-type Landrace pigs and high serum testosterone-type Meishan and Landrace/Meishan-crossbreed (LM and ML) pigs. Testicular mRNA levels of the enzymes (3-hydroxy-3-methylglutaryl-CoA synthase 1 and 3-hydroxy-3-methylglutaryl-CoA reductase) and proteins (low density lipoprotein receptor and scavenger receptor class B member 1) affecting intracellular levels of cholesterol, a precursor of testosterone, were 2-5-fold higher in Meishan, LM and ML pigs than in Landrace pigs. Likewise, the mRNA levels of steroidogenic acute regulatory protein, which imports cholesterol to the inner mitochondrial membrane, and of testosterone biosynthesis enzymes (CYP11A1 and CYP17A1) were over 10-fold and approximately 3-fold higher, respectively, in Meishan, LM and ML pigs than in Landrace pigs. Furthermore, positive correlations between those mRNA levels and serum testosterone levels were observed. Despite large breed differences in testicular mRNA levels described above, no significant breed differences in intratesticular testosterone levels were observed. The present findings strongly suggest that breed differences in serum testosterone levels of male pigs are probably, at least in part, caused by differences in testicular mRNA levels of enzymes and proteins involved in testosterone biosynthesis process and by differences in the levels of testosterone released from testes.

Recessive mutation on mouse chromosome 13 associated with abnormal hair texture and cardiomyopathy.

An autosomal recessive mutation (aht) associated with abnormal hair texture and cardiomyopathy spontaneously arose in the Y-chromosome consomic mouse strain DH-Chr YSS . The aht/aht mouse phenotypes closely resembled those of rul/rul mice, which were caused by a mutation in desmoplakin (Dsp) on chromosome 13. Quantitative trait locus (QTL) mapping using (DDD/Sgn × DH-Chr YSS -aht heterozygotes) F2 mice demonstrated that aht is contiguous with Dsp on chromosome 13. However, no nucleotide changes were identified in the coding region of Dsp in aht/aht mice by whole-exome sequencing. Therefore, the molecular nature of the aht mutation remains unclear. Nevertheless, aht/aht mice may serve as a new model for human diseases that are accompanied by abnormalities in the integumental and cardiovascular systems, including Carvajal-Huerta syndrome.

Identification of a novel mutant allele of LIM homeobox transcription factor 1 alpha (dreher) in mice.

A male mouse exhibiting bidirectional circling behavior was identified in a Y-chromosome consomic strain known as DH-Chr YRR . The putative mutation responsible for the circling behavior was inherited in an autosomal recessive manner and was termed circ. To identify its causative gene, we performed exome sequencing; of the 34 candidates discovered, we found a novel nonsynonymous single nucleotide variation in LIM homeobox transcription factor 1 alpha (Lmx1a) (c.394G > C, p.Gly132Arg). The genetic linkage between Lmx1a and circ was confirmed in (♀BALB/cA × â™‚DH-Chr YRR -circ/circ) F2 and (♀C57BL/6J × â™‚DH-Chr YRR -circ/circ) F2 mice. The Lmx1a mutation led to many abnormalities that affected growth, pigmentation, reproduction, and cerebellar morphology. We showed that (♀BALB/cA × â™‚DH-Chr YRR -circ/circ) F2 -circ/circ mice demonstrated significantly lower body mass than the F2 -+/? mice. Unlike the F2 -+/? mice, few (♀C57BL/6J × â™‚DH-Chr YRR -circ/circ) F2 -circ/circ mice exhibited a belly spot. The circ/circ females were also invariably sterile, probably because of an underdeveloped uterus. Moreover, the circ/circ mice presented fewer cerebellar granule cells with lower density than the F2 -+/? mice. Although non-complementation between circ and the known Lmx1a mutant alleles remains unconfirmed, the coisogenic nature of circ strongly suggests that it is a novel variant of Lmx1a, previously known as dreher. Therefore, we have assigned the gene symbol Lmx1adr-circ to circ. In addition to Lmx1adr-J and Lmx1adr-kjmi , Lmx1adr-circ is the third allele that causes a missense mutation within LIM domains. Identification of missense mutations is necessary to specify the critical residues for abrogating the in vivo functions of LMX1A.

Low pup survival rate is associated with maternal Naq3 genotype and hypothalamic Vps8 expression levels in mice.

Pups born from females of the inbred mouse strain RR/Sgn tend to have low survival rates during rearing. We have previously identified Naq3, a quantitative trait locus underlying this low pup survival rate. In the present study, we confirmed the effect of Naq3 in congenic mice and investigated whether Vps8 is a candidate gene for Naq3. The survival rate of pups on the twelfth postpartum day was significantly decreased for mothers homozygous for the Naq3 allele. Hypothalamic expression of Vps8 was induced by nurturing in wild-type mice, and was significantly lower in Naq3 congenic mice than in wild-type mice. Thus, Vps8 is suggested to be involved in maternal nurturing, and therefore, as a plausible candidate gene for Naq3.

Genetic analysis of the mandible morphology in DDD.Cg-Ay/Sgn and C57BL/6J inbred mice.

Quantitative trait loci (QTL) mapping analysis was performed for the mandible morphology in DDD.Cg-Ay/Sgn and C57BL/6J inbred mice. The size and shape of the mandible was analysed by landmark-based geometric morphometrics as the centroid size and principal components (PCs), respectively. The Ay allele at the agouti locus significantly reduced the mandible size in DDD/Sgn background, and substantially altered the mandible shape in both strain backgrounds. Single-QTL scans, by including the agouti locus genotype (Ay or non-Ay) as an additive covariate, identified three significant QTL for the centroid size on chromosomes 5, 6 and 17, along with four suggestive QTL on chromosomes 2, 12, 18 and 19. These QTLs explained 46.85% of the centroid size variation in F2 mice. When the F2Ay and F2 non-Ay mice were analysed separately, additional significant QTL were identified on chromosomes 12 and 15 in F2 non-Ay mice. Single-QTL scans also identified 15 significant QTL for the PC1, PC2 and PC3. When the agouti locus genotype was included as an interactive covariate, nine significant QTLs were identified. Unexpectedly, these agouti-interacting QTLs were identified for relatively minor PCs, for which no significant single-QTL were identified. Therefore, it was suggested that the alteration of the mandible shape in Ay mice was the consequence of interactions between the Ay allele and genes that themselves have relatively small phenotypic effect. Although further in vivo studies are required, we postulated Pkd1 as a possible candidate gene underlying QTL for the centroid size on chromosome 17.

Effects of quantitative trait loci determining testicular weight in DDD/Sgn inbred mice are strongly influenced by circulating testosterone levels.

OBJECTIVE: Testicular growth and development are strongly influenced by androgen. Although both testis weight and plasma testosterone level are inherited traits, the interrelationship between them is not fully established. Males of DDD/Sgn (DDD) mice are known to have extremely heavy testes and very high plasma testosterone level among inbred mouse strains. We dissected the genetic basis of testis weight and analyzed the potential influence of plasma testosterone level in DDD mice. METHODS: Quantitative trait loci (QTL) mapping of testis weight was performed with or without considering the influence of plasma testosterone level in reciprocal F2 intercross populations between DDD and C57BL/6J (B6) mice, thereby assessing the influence of testosterone on the effect of testis weight QTL. Candidate genes for testis weight QTL were investigated by next-generation sequencing analysis. RESULTS: Four significant QTL were identified on chromosomes 1, 8, 14, and 17. The DDD-derived allele was associated with increased testis weight. The F2 mice were then divided into two groups according to the plasma testosterone level (F2 mice with relatively "low" and "high" testosterone level), and QTL scans were again performed. Although QTL on chromosomes 1 was shared in both F2 mice, QTL on chromosomes 8 and 17 were identified specifically in F2 mice with relatively high testosterone levels. By whole-exome sequencing analysis, we identified one DDD-specific missense mutation Pro29Ser in Atat1. CONCLUSION: Most of the testis weight QTL expressed stronger phenotypic effect when they were placed on circumstance with high testosterone level. High testosterone influenced the QTL by enhancing the effect of DDD-derived allele and diminishing the effects of B6-derived allele. Since Pro29Ser was not identified in other inbred mouse strains, and since Pro29 in Atat1 has been strongly conserved among mammalian species, Atat1 is a plausible candidate for testis weight QTL on chromosome 17.

Effects of the Y-chromosome and the dominant hemimelia mutation on the morphology of the mouse mandible.

The aims of this study were to test whether the Y-chromosome and the autosomal dominant hemimelia (Dh) mutation can affect mandible morphology in mice. I analyzed mandible size and shape using landmark-based geometric morphometrics in 16 DH-Chr Y@ -+/+ (@ represents one of the inbred strain names) strains and observed significant differences in mandible size. The largest mandible was identified in strain DH-Chr YC3H and the smallest in strain DH-Chr YKK . Canonical variate and discriminant function analyses suggested that the mandible shapes of strains DH-Chr YC3H and DH-Chr YKK differed from those of the other strains. Because seven of the DH-Chr Y@ -+/+ strains were maintained with dominant hemimelia, I also analyzed the potential influence of dominant hemimelia on mandible morphology because dominant hemimelia is known to cause various skeletal malformations. There were no significant differences in mandible size in seven sets of DH-Chr Y@ -+/+ and DH-Chr Y@ -Dh/+ strains. However, canonical variate analysis mapped strains DH-Chr YCAS -Dh/+ and DH-Chr YCBA -Dh/+ mapped distantly from the rest. Additionally, I observed similar patterns of shape change between DH-Chr YCAS -+/+ and DH-Chr YCAS -Dh/+, and between DH-Chr YCBA -+/+ and DH-Chr YCBA -Dh/+. These data indicate that the Y-chromosome affects the size and shape of the mouse mandible. Dominant hemimelia affects mandible shape but not size, and its effects emerge depending on the kinds of Y-chromosomes.

Quantitative trait loci that determine plasma insulin levels in F2 intercross populations produced from crosses between DDD/Sgn and C57BL/6J inbred mice.

When compared to C57BL/6J (B6) mice, DDD/Sgn (DDD) mice has substantially higher plasma insulin levels in both sexes. In this study, we performed quantitative trait loci (QTL) mapping of plasma insulin levels in F2 male mice produced by crosses between DDD and B6 mice. By single-QTL scans, we identified one significant QTL on chromosome 9. When body weight was included as an additive covariate, we identified two significant QTL on chromosomes 9 and 12; the latter coincided with a QTL that was previously identified in F2 female mice produced by the same two strains. The inheritance mode and the direction of the allelic effect of QTL on chromosome 12 were similar in both sexes, but those on chromosome 9 differed between males and females, suggesting that the QTL on chromosome 9 was sex-specific. Based on phenotypic correlations of plasma insulin levels with body weight and plasma levels of total cholesterol, triglyceride and testosterone, we subsequently assessed whether these insulin QTL explain the variation in other metabolic traits by using a point-wise significance threshold of P = 0.05. QTL on chromosome 12 had no significant effect on any trait. In contrast, QTL on chromosome 9 had significant effects on body weight and total cholesterol level. We postulate that Gpr68 and Cyp19a1 are plausible candidate genes for QTL on chromosomes 12 and 9, respectively. These findings provide insight into the genetic mechanisms underlying insulin metabolism.

Identification of Quantitative Trait Loci That Determine Plasma Total-Cholesterol and Triglyceride Concentrations in DDD/Sgn and C57BL/6J Inbred Mice.

DDD/Sgn mice have significantly higher plasma lipid concentrations than C57BL/6J mice. In the present study, we performed quantitative trait loci (QTL) mapping for plasma total-cholesterol (CHO) and triglyceride (TG) concentrations in reciprocal F2 male intercross populations between the two strains. By single-QTL scans, we identified four significant QTL on chromosomes (Chrs) 1, 5, 17, and 19 for CHO and two significant QTL on Chrs 1 and 12 for TG. By including cross direction as an interactive covariate, we identified separate significant QTL on Chr 17 for CHO but none for TG. When the large phenotypic effect of QTL on Chr 1 was controlled by composite interval mapping, we identified three additional significant QTL on Chrs 3, 4, and 9 for CHO but none for TG. QTL on Chr 19 was a novel QTL for CHO and the allelic effect of this QTL significantly differed between males and females. Whole-exome sequence analysis in DDD/Sgn mice suggested that Apoa2 and Acads were the plausible candidate genes underlying CHO QTL on Chrs 1 and 5, respectively. Thus, we identified a multifactorial basis for plasma lipid concentrations in male mice. These findings will provide insight into the genetic mechanisms of plasma lipid metabolism.

Locus on chromosome 16 is significantly associated with increased tendency to lose pups in females of the RR/Sgn inbred mouse strain.

Females of the inbred mouse strain RR/Sgn have an apparent tendency to lose pups during rearing. To identify genes underlying this abnormal maternal phenotype, we performed quantitative trait loci (QTL) mapping in 349 (C57BL/6 J × RR/Sgn) F1  × RR/Sgn backcross mice and identified one significant and one suggestive QTL on chromosomes 16 and 4, respectively. We assigned the gene symbol nurturing ability QTL 3 (Naq3) to the QTL on chromosome 16. Twenty of the 21 mothers who lost entire litters were homozygous for RR/Sgn allele at Naq3; i.e., the significant association of Naq3 with pup loss was further confirmed by binomial tests. We tentatively propose that Mapk1, Kalrn, and Vps8 are potential candidate genes for Naq3.

Quantitative trait loci that control body weight in DDD/Sgn and C57BL/6J inbred mice.

Inbred DDD/Sgn mice are heavier than inbred C57BL/6J mice. In the present study, we performed quantitative trait loci (QTL) mapping for body weight using R/qtl in reciprocal F2 male populations between the two strains. We identified four significant QTL on Chrs 1, 2, 5, and 17 (proximal region). The DDD/Sgn allele was associated with increased body weight at QTL on Chrs 1 and 5, and the DDD/Sgn allele was associated with decreased body weight at QTL on Chrs 2 and 17. A multiple regression analysis indicated that the detected QTL explain 30.94 % of the body weight variation. Because DDD/Sgn male mice have extremely high levels of circulating testosterone relative to other inbred mouse strains, we performed QTL mapping for plasma testosterone level to examine the effect of testosterone levels on body weight. We identified one suggestive QTL on Chr 5, which overlapped with body weight QTL. The DDD/Sgn allele was associated with increased testosterone level. Thus, we confirmed that there was a genetic basis for the changes in body weight and testosterone levels in male mice. These findings provide insights into the genetic mechanism by which body weight is controlled in male mice.

Genetic analysis of low survival rate of pups in RR/Sgn inbred mice.

Newborn offspring of the inbred mouse RR/Sgn strain have a low survival rate prior to weaning. We hypothesized that this is a consequence of an inferior nurturing ability of RR/Sgn mothers and that RR/Sgn mothers have a tendency to lose their pups. We performed quantitative trait locus (QTL) mapping for inferior nurturing ability and tendency to lose pups in RR/Sgn mothers. The number of pups was adjusted to 6 per dam on the day of delivery, and the number of surviving pups and their total weight (litter weight) were scored at 12 days after birth. Nurturing ability was evaluated by litter weight, and tendency to lose pups was evaluated by scoring whether or not the mothers lost their pups. For litter weight, we identified one significant QTL on chromosome 4 and three suggestive QTLs on chromosomes 7, 9 and 17. The RR/Sgn allele was associated with lower litter weight at all loci. For the tendency to lose pups, we identified three suggestive QTLs on chromosomes 4, 9 and 16. The RR/Sgn allele was associated with an increased tendency to lose pups at all loci. These results supported our hypothesis that the low survival rate phenotype was attributable, at least in part, to a phenotype whereby mothers display inferior nurturing ability and a tendency to lose pups. Thus, it suggests that these two traits share genetic basis.

Effect of the Y chromosome on testis weight in mice.

We investigated the effect of the Y chromosome on testis weight in (B6.Cg-A(y) × Y-consomic mouse strain) F1 male mice. We obtained the following results: (1) Mice with the Mus musculus domesticus-type Y chromosome had significantly heavier testis than those with the M. m. musculus-type Y chromosome. (2) Variations in Usp9y and the number of CAG repeats in Sry were significantly associated with testes weight. The A(y) allele was correlated with a reduced testis weight, and the extent of this reduction was significantly associated with a CAG repeat number polymorphism in Sry. These results suggest that Y chromosome genes not only influence testis weight but also modify the effect of the A(y) allele in mediating this phenomenon.

Further characterization of diabetes mellitus and body weight loss in males of the congenic mouse strain DDD.Cg-A(y.).

The A(y) allele at the agouti locus causes obesity and promotes linear growth in mice. However, body weight gain stops between 16 and 17 weeks after birth, and then, body weight decreases gradually in DDD.Cg-A(y) male mice. Body weight loss is a consequence of diabetes mellitus, which is genetically controlled mainly by a quantitative trait locus (QTL) on chromosome 4. This study aimed to further characterize diabetes mellitus and body weight loss in DDD.Cg-A(y) males. The number of ß-cells was markedly reduced, and plasma insulin levels were very low in the DDD.Cg-A(y) males. Using a backcross progeny of DDD × (B6 × DDD.Cg-A(y)) F1-A(y), we identified one significant QTL for plasma insulin levels on distal chromosome 4, which was coincidental with QTL for hyperglycemia and lower body weight. The DDD allele was associated with decreased plasma insulin levels. When the DDD.Cg-A(y) males were housed under three different housing conditions [group housing (4 or 5 DDD.Cg-A(y) and DDD males), individual housing (single DDD.Cg-A(y) male) and single male housing with females (single DDD.Cg-A(y) male with DDD.Cg-A(y) or DDD females)], diabetes mellitus and body weight loss were most severely expressed in individually housed mice. Thus, the severity of diabetes and body weight loss in the DDD.Cg-A(y) males was strongly influenced by the housing conditions. These results demonstrate that both genetic and nongenetic environmental factors are involved in the development of diabetes mellitus and body weight loss in the DDD.Cg-A(y) males.

Genetic analysis of litter size in mice.

We performed quantitative trait locus (QTL) mapping analysis for litter size (total number of pups born and/or number of pups born alive) in 255 backcross mice derived from C57BL/6J and RR/Sgn inbred mice. We identified one significant QTL on chromosome 7 and 4 suggestive QTLs on chromosomes 3, 5, 10 and 13. In addition, two suggestive QTLs were identified on chromosomes 1 and 4 for the number of stillbirth. These results suggested that both litter size and number of stillbirth were heritable traits, although they were controlled by distinct genes. The RR allele was associated with reduced litter size and increased stillbirth at all QTLs. Therefore, RR mothers were observed to have reduced prolificacy in this particular genetic cross.

Effect of the Y chromosome on plasma high-density lipoprotein-cholesterol levels in Y-chromosome-consomic mouse strains.

BACKGROUND: Plasma high-density lipoprotein (HDL)-cholesterol level is a clinically important quantitative phenotype that widely varies among inbred mouse strains. Several genes or loci associated with plasma HDL-cholesterol levels have been identified on autosomes and the X chromosome. In contrast, genes or loci on the Y chromosome have not attracted significant attention hitherto. Therefore, we investigated the effects of the Y chromosome on plasma HDL-cholesterol levels in Y- chromosome-consomic (Y-consomic) mouse strains. FINDINGS: Plasma HDL-cholesterol level data from 16 Y-consomic strains demonstrated that the Y chromosome substitutions significantly altered plasma HDL-cholesterol levels, i.e., variations in the plasma HDL-cholesterol level could be partially explained by Y chromosome genes. We obtained the following results from the genotype data on 30 single nucleotide polymorphisms (SNPs), including nonsynonymous and synonymous SNPs and 9 polymorphisms in Sry: (1) Variation in rs46947134 of Uty was significantly associated with plasma HDL-cholesterol levels. (2) A CAG repeat number polymorphism in Sry was significantly associated with plasma HDL-cholesterol levels. (3) Strains with a certain haplotype of the Mus musculus domesticus-type Y chromosome had significantly lower plasma HDL-cholesterol levels than strains with a certain haplotype of the M. m. musculus-type Y chromosome. CONCLUSIONS: The effect of the Y chromosome on plasma HDL-cholesterol levels was confirmed in the Y-consomic strains. We identified several variants associated with plasma HDL-cholesterol levels. Because the physiological significance of various Y-linked genes remains unclear, the results of this study will provide further insights into the functions of Y-linked genes in lipid metabolism.

Genetic background (DDD/Sgn versus C57BL/6J) strongly influences postnatal growth of male mice carrying the A(y) allele at the agouti locus: identification of quantitative trait loci associated with diabetes and body weight loss.

BACKGROUND: Mice carrying the A(y) allele at the agouti locus become obese and are heavier than their non-A(y) littermates. However, this does not hold true for the genetic background of the DDD mouse strain. At 22 weeks of age, DDD.Cg-A(y) females are heavier than DDD females, whereas DDD.Cg-A(y) males are lighter than DDD males. This study aimed to determine the possible cause and identify the genes responsible for the lower body weight of DDD.Cg-A(y) males. RESULTS: Growth curves of DDD.Cg-A(y) mice were analyzed and compared with those of B6.Cg-A(y) mice from 5 to 25 weeks. In DDD.Cg-A(y) males, body weight gain stopped between 16 and 17 weeks and the body weight gradually decreased; thus, the lower body weight was a consequence of body weight loss. Quantitative trait locus (QTL) mapping was performed in backcrossed (BC) males of DDD × (B6 × DDD.Cg-A(y)) F(1)-A(y) mice. For the body weight at 25 weeks, significant QTLs were identified on chromosomes 1 and 4. The DDD allele was associated with a lower body weight at both loci. In particular, the QTL on chromosome 4 interacted with the A(y) allele. Furthermore, suggestive QTLs for plasma glucose and high molecular weight adiponectin levels were coincidentally mapped to chromosome 4. The DDD allele was associated with increased glucose and decreased adiponectin levels. When the body weight at 25 weeks and plasma glucose levels were considered as dependent and independent variables, respectively, BC A(y) males were classified into two groups according to statistical analysis using the partition method. Mice of one group had significantly higher glucose and lower adiponectin levels than those of the other group and exhibited body weight loss as observed with DDD-A(y) males. CONCLUSIONS: The lower body weight of DDD.Cg-A(y) male mice was a consequence of body weight loss. Diabetes mellitus has been suggested to be a possible contributory factor causing body weight loss. The QTL on distal chromosome 4 contained the major responsible genes. This QTL interacted with the Ay allele, implying the reason why body weight loss occurs in DDD.Cg-Ay but not in DDD males.

QTL mapping of genes controlling plasma insulin and leptin concentrations: metabolic effect of obesity QTLs identified in an F2 intercross between C57BL/6J and DDD.Cg-A(y) inbred mice.

DDD.Cg-A(y) female mice developed massive obesity as compared with B6.Cg-A(y) female mice. We previously identified quantitative trait loci (QTLs) for obesity on chromosomes 1, 6, 9 and 17 in F2 female mice, including F2A(y) (F2 mice with the A(y) allele) and F2 non- A(y) mice (F2 mice without the A(y) allele), produced by crossing C57BL/6J and DDD.Cg-A(y) strains. We here addressed the question whether the obesity QTLs share genetic bases with putative QTLs for plasma glucose, insulin and leptin concentrations. We performed QTL analyses for the first principal component (PC1) extracted from these metabolic measurements to identify the genes that contributed to the comprehensive evaluation of metabolic traits. By single QTL scans, we identified two significant QTLs for insulin concentration on chromosomes 6 and 12, three for leptin concentration on chromosomes 1, 6 and 17, and five for PC1 on chromosomes 1, 6, 12 (two loci) and 17. Although insulin and leptin concentrations and PC1 were not normally distributed in combined F2 mice, results of single QTL scans by parametric and non-parametric methods were very similar. Therefore, QTL scan by the parametric method was performed with the agouti locus genotype as a covariate. A significant QTL × covariate interaction was found for PC1 on chromosome 9. All obesity QTLs had significant metabolic effects. Thus, obesity- and diabetes-related traits in DDD.Cg-A(y) mice were largely controlled by QTLs on chromosomes 1, 6, 9, 12 and 17.

Y chromosome of the inbred mouse KK/Ta strain is associated with reduced body size in Y-consomic strains.

BACKGROUND: We have established 17 Y chromosome consomic (Y-consomic) mouse strains in an inbred DH/Sgn strain. In this study, based on investigations in four different genetic backgrounds, we proved that the Y chromosome of the inbred mouse KK/Ta strain is associated with reduced body size. FINDINGS: In the DH-Chr Y-+/+ background, Y chromosome substitution significantly decreased the body weight in DH-Chr Y(KK)-+/+ and DH-Chr Y(SJL)-+/+ strains, and the DH-Chr Y(KK)-+/+ strain was the lightest among the 17 Y-consomic strains. In the DH-Chr Y-Dh/+ background (Dh/+ mice have skeletal malformations and are usually lighter than +/+ mice), although Y chromosome substitution did not significantly alter the body weight, the DH-Chr Y(KK)-Dh/+ strain was the lightest among the 17 Y-consomic-Dh/+ strains. In the (B6.Cg-A(y) × DH-Chr Y) F1-+/+ background, Y chromosome substitution significantly decreased the body weight and length in the (B6.Cg-A(y) × DH-Chr Y(KK)) F1 hybrids. In the (B6.Cg-A(y) × DH-Chr Y) F1-A(y)/+ background (Ay causes obesity and promotes linear growth), Y chromosome substitution significantly decreased body weight and length in the (B6.Cg-A(y) × DH-Chr Y(KK)) F1-A(y)/+ hybrids. CONCLUSION: A body-size-reducing effect of the Y chromosome of the KK/Ta mouse strain was observed irrespective of genetic background. The effect was observed in the presence of Dh and A(y), the autosomal dominant mutations, both of which are known to have substantial effects on body size. These results suggest that there are Y-linked genes that control the body size in mice.