Table 5. QTL Positional Candidate Genes.
Positional candidate genes are listed for each QTL by QTL name and trait affected (H, humerus; U, ulna; F, femur; T, tibia). The length of the pleiotropic QTL confidence interval (CI; given in bp), the number of genes in the confidence interval, and the number of polymorphisms between LG/J and SM/J that fall in the CI are listed. The genes of interest include genes from families known to contribute to skeletal growth or cellular morphology (see Results). Underlining indicates that a SNP was identified in the coding region of the gene, while boldface indicates the presence of an amino-acid changing mutation(s).
| QTL | Trait | CI | Genes | SNPs | Genes of Interest |
|---|---|---|---|---|---|
| Lbn1.2 | UF | 13,735,703 | 61 | 22,548 | Rdh10 |
| Lbn1.3 | HFT | 9,098,689 | 75 | 36,819 | |
| Lbn1.1a | UFT | 6,084,606 | 53 | 16,044 | Atg9a, Chpf, Cul3, Ihh, Pax3 |
| Lbn1.1a | H | 1,941,869 | 33 | 4,079 | Rufy4, Tmbim1, Wnt10a, Wnt6 |
| Lbn1.1b | HFT | 6,943,123 | 69 | 8,323 | Akp5, Atg16l1, Cab39, Dner, Trip12 |
| Lbn2.4 | HUFT | 666,122 | 5 | 1,161 | 6330527O06Rik, Pak7, Plcb4 |
| Lbn2.1a | UT | 4,127,540 | 20 | 5,245 | Fibin, Kif18a |
| Lbn2.1b | T | 1,087,635 | 4 | 1,886 | Aven, Fmn1, Ryr3 |
| Lbn2.1b | HUF | 1,581,121 | 8 | 2,696 | Actc1, Aqr, Arhgap11a, Atpbd4, Gjd2, Scg5, Zfp770 |
| Lbn2.1c | HUFT | 12,146,034 | 178 | 35,894 | 1500003O03Rik, Bmf, Capn3, Ccndbp1, Dnajc17, Mapkbp1, Meis2 |
| Lbn2.3a | HUFT | 3,172,374 | 8 | 7,841 | 2310003L22Rik, Btbd3, Esf1, Ism1, Macrod2, Sel1l2, Sptlc3, Tasp1 |
| Lbn2.3b | HUFT | 3,370,609 | 74 | 9,308 | Bcl2l1, Gm1006, Kif3b, Rya3, Sox12 |
| Lbn3.3 | U | 1,021,539 | 0 | 1,203 | |
| Lbn3.2a | HUFT | 6,918,457 | 180 | 2,980 | Adamts14, Bnipl, Ecm1, Npr1, Snapin, Tnfaip8l2 |
| Lbn4.1 | HUFT | 6,490,909 | 50 | 15,426 | Insl5, Lepr, Leprot, Oma1 |
| Lbn4.2 | HUFT | 4,844,329 | 101 | 25,700 | Gmeb1, Map3k6, Matn1, Rcan3, Runx3 |
| Lbn4.3 | HUFT | 9,312,256 | 13 | 18,282 | Megf9, Tlr4, Tnfsf15, Tnfsf8 |
| Lbn4.4 | HFT | 1,778,278 | 48 | 4,398 | Cdc20 |
| Lbn4.5 | HFT | 2,165,219 | 29 | 5,894 | Snip1 |
| Lbn6.2 | UFT | 3,663,784 | 20 | 10,087 | 1700023A16Rik, 1700034J05Rik, 2210417D09Rik, 4933424B01Rik, Arntl2, EG545893, Fgfr1op2, Itpr2, Klhdc5, Med21, Mrps35, Ppfibp1, Pthlh, Skt38l, Tm7sf3 |
| Lbn6.2 | H | 1,132,711 | 15 | 31,262 | Sox5 |
| Lbn6.3 | HUFT | 1,956,305 | 20 | 537 | Hdac11, Wnt7a |
| Lbn6.1a | FT | 3,344,981 | 24 | 7,316 | Cadps2, Hyal4, Hyal5, Hyal6, Ing3, Spam1, Wnt16 |
| Lbn7.1 | HUFT | 6,276,356 | 89 | 15,784 | Hapln3, Mesdc1, Mesdc2, Mesp1, Mesp2, Rlbp1 |
| Lbn7.3 | HUFT | 3,056,930 | 20 | 7,935 | Adamts17, Chsy1, Igf1r |
| Lbn7.4 | HUFT | 8,808,703 | 93 | 6,125 | Sox6 |
| Lbn8.2 | HU | 1,709,669 | 21 | 950 | |
| Lbn8.1a | HFT | 1,197,007 | 9 | 496 | Cilp2, Comp, Csgalnact1, Gdf1, Gdf15, Insl3, Jund |
| Lbn8.1a | U | 2,446,181 | 9 | 5,184 | |
| Lbn8.1b | UF | 4,608,981 | 23 | 18,965 | Hapln4, Hhip |
| Lbn9.2 | HUFT | 3,806,152 | 31 | 4,574 | Adam10, Aldh1a2, Bnip2 |
| Lbn9.3 | HUFT | 5,433,606 | 50 | 40,323 | Pcolce2, Rbp1, Rbp2, Sox14 |
| Lbn10.1 | HFT | 2,980,044 | 33 | 6,438 | Igf1, Timp3 |
| Lbn10.2 | UT | 2,257,783 | 105 | 8,839 | Cdk2, Gdf11, Hsd17b6, Itga7, Mmp19, Os9, Rdh1, Rdh5, Rdh7, Rdh9, Rdh16, Rdh19, Stat2, Stat6 |
| Lbn11.1 | HU | 3,350,369 | 5 | 7,092 | Egfr, Meis1 |
| Lbn11.2 | HUF | 8,839,855 | 131 | 14,294 | Adamts2, Col23a1, Flt4, Gdf9, Kif3a, Mapk9 |
| Lbn11.2 | T | 3,886,126 | 74 | 9,493 | Sap30l |
| Lbn12.1 | HUFT | 4,019,008 | 27 | 7,320 | Mbip, Nfkbia, Nkx2-1, Nkx2-9, Pax9 |
| Lbn12.2 | U | 2,241,976 | 10 | 5,557 | |
| Lbn12.3 | HUFT | 3,895,541 | 40 | 10,749 | Cdkl1, Map4k5 |
| Lbn12.4 | HUFT | 3,961,529 | 33 | 2,730 | Esr2, Rdh11, Rdh12 |
| Lbn12.5 | T | 4,642,071 | 63 | 1,352 | Fos, Ltbp2, Pgf, Tgfb3 |
| Lbn13.1 | HUFT | 5,458,185 | 35 | 7,926 | Adamts6, Ccnb1, Rad17 |
| Lbn14.1 | HUFT | 5,450,897 | 5 | 21,697 | Diap3, Pcdh17, Pcdh20, Tdrd3 |
| Lbn15.2 | HUFT | 3,169,700 | 15 | 7,953 | Kif21a |
| Lbn15.3 | HU | 3,249,196 | 18 | 4,716 | Col14a1, Has2 |
| Lbn18.2 | HFT | 1,635,348 | 8 | 1,348 | |
| Lbn18.1a | HUFT | 5,391,984 | 35 | 10,052 | Nr3c1 |
| Lbn18.1b | U | 9,241,364 | 51 | 18,924 | Atg12 |
| Lbn19.1 | HUFT | 4,475,262 | 161 | 1,395 | Atg2a, Bad, Capn1, Efemp2, Esrra, Fibp, Fosl1, Kat5, Ltbp3, Map3k11, Map4k2, Vegfb |
Interestingly, while we expected to identify QTL with confidence intervals of ~0.5 F2 cM, actual confidence intervals averaged ~1.7 F2 cM (corresponding to ~4.5 Mb). In terms of physical distances, the confidence intervals ranged from 14 Mb for the largest QTL (Lbn1.2) to 0.6 Mb for the smallest QTL (Lbn2.4), with about half of the QTL having confidence intervals between 2 and 5 Mb (see Table 5). There are several possible reasons for the apparent lack of increased resolution between the F9-10 and F34 generations. First, as opposed to the previous studies on which the 0.5 F2 cM estimate was based, the parental generation (F33) was not included in the mapping population because it was not subject to the same dietary treatments. As discussed in the previous studies, familial autocorrelation inflated QTL peak size and this did impact how confidence intervals were set in earlier generations. While all F34 individuals are related and thus subject to familial autocorrelation, the absence of the parental generation should have decreased QTL peak inflation relative to previous generations. A second possibility is that some QTL are caused by multiple linked genomic elements. While several of the QTL reported above have short confidence intervals with few (≥ 10) or no candidate genes (Lbn2.1b, Lbn2.3a, Lbn2.4, Lbn3.3, Lbn8.1a, Lbn11.1, Lbn12.2, Lbn14.1, and Lbn18.2), the majority have between 20 and 70 candidate genes (listed in Table 5). The absence of most of the known major endochondral ossification regulators within the confidence intervals supports the idea that genes controlling normal cellular processes such as metabolism, motility, or cell division have a measurable cumulative effect on cellular dynamics. Given the nature of bone elongation via the growth plate, this finding is not unreasonable.