Retention of juvenile traits in the adult reproductive phase characterizes a process known as neoteny, and speculation exists over whether it has contributed to the evolution of new species. The dominant Corngrass1 (Cg1) mutant of maize is a neotenic mutation that results in phenotypes that may be present in the grass-like ancestors of maize. We cloned Cg1 and found that it encodes two tandem miR156 genes that are overexpressed in the meristem and lateral organs. Furthermore, a target of Cg1 is teosinte glume architecture1 (tga1), a gene known to have had a role in the domestication of maize from teosinte. Cg1 mutant plants overexpressing miR156 have lower levels of mir172, a microRNA that targets genes controlling juvenile development. By altering the relative levels of both microRNAs, it is possible to either prolong or shorten juvenile development in maize, thus providing a mechanism for how species-level heterochronic changes can occur in nature.

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In the present study, we investigated the relationship between the KIR loci and the genes encoding their HLA ligands and genetic susceptibility to Crohn's disease (CD). Analyses of the interactions between KIR3DL1, KIR2DL1, KIR2DL2 and KIR2DL3 with their respective HLA ligands indicate that there is a protective effect for KIR2DL2 in the absence of its HLA ligand C1. Given that KIR2DL2 and KIR2DL3 segregate as alleles, we compared their genotypic distributions to expectations under Hardy-Weinberg Equilibrium (HWE) with regard to the HLA ligand C1 status. While all the genotypic distributions conform to expectations under HWE in controls, in C2 ligand homozygous cases there is significant deviation from HWE, with a reduction of KIR2DL2, KIR2DL3 heterozygotes. KIR2DL2, KIR2DL3 heterozygosity is the only genotypic combination that confers protection from CD. In addition to the protective effect (OR = 0.44, CI = 0.22-0.87; p = 0.018) observed in C2 ligand homozygotes, the KIR2DL2, KIR2DL3 genotype is predisposing (OR = 1.34, CI = 1.03-4.53; p = 0.031) in the presence of C1 ligand. A test for trend of HLA class I C ligand group genotypes with KIR2DL2, KIR2DL3 heterozygosity in cases and controls indicates that C1, C2 ligand group heterozygotes have an intermediate effect on predisposition. These results show for the first time that disease susceptibility may be related to heterozygosity at a specific KIR locus, and that HLA ligand genotype influences the relative effect of the KIR genotype.

The importance of killer immunoglobulin-like receptors (KIR) in determining clinical outcome after hematopoietic cell transplantation (HCT) remains controversial. We analyzed 428 unrelated, T-cell replete transplants for acute myeloid leukemia (AML) facilitated by the National Marrow Donor Program between 1988 and 2003. Fifty seven KIR-ligand mismatched (thus HLA mismatched; KIR-Lmm/HLAmm) transplants were selected as cases. By matching on 15 clinical and demographic variables, KIR ligand matched, HLA mismatched (KIR-Lm/HLAmm; n = 162) and 10/10 HLA matched (HLAm; n = 209) comparison groups were selected. Using a validated single nucleotide polymorphism (SNP)-based MALDI-TOF assay, DNA samples were typed for 16 individual KIR genes which were used to estimate KIR haplotypes. About 1/3 of donors and recipients were A/A (lacking any activating KIR except 2DS4) and 2/3 possessed at least one B haplotype (B/X). As expected, 3 year survival was better in HLAm vs. HLAmm KIR-Lm or KIR-Lmm HCT (32%; p = .07 and 0.0004 respectively). However, survival was similar in both HLAmm groups (KIR-Lm 27% vs. KIR-Lmm 17%; p = .11). Importantly, transplants from donors with an activating B KIR haplotype had significantly better survival. Using a Cox regression that stratifies the baseline hazard according to sets of patients matched on important clinical variables, transplants using B KIR haplotype donors had a 42% reduced risk of mortality [B/X (vs. A/A) KIR haplotype donors (RR .58, 95% CI .44–.78; p = .0002]. Similarly, for disease-free survival (DFS), the risk of relapse and/or death decreased 43% [B/X (vs. A/A) RR .57, 95% CI .43–.76; p = .0001]. No differences were seen in risks of acute GVHD. The significant improvements in overall survival and DFS conferred by donor B KIR haplotype were seen in both the HLAm and KIR-Lm/HLAmm groups, but not in the KIR-Lmm/HLAmm group. The recipient KIR haplotype had no effect on outcomes, and the benefit of donor B KIR haplotype was equal regardless of recipient KIR haplotype (figure). Individual KIR genes were also analyzed and in Cox regression only donor 2DL2 and 2DS2 were favorable. As these genes are in strong linkage disequilibrium, the effects were similar (donor 2DL2 RR of death .70, 95% CI .54–.91; p = .008 and 2DS2 RR .66, 95% CI .50–.86; p = .002). 2DS2 defines a B KIR haplotype, confounding interpretation of these single gene effects. In summary, data from this analysis of the effect of KIR genes in unrelated T-replete HCT for AML suggest that using B KIR haplotype donors improves survival and DFS. Therefore, KIR genotyping could be incorporated into unrelated donor selection algorithms to identify B haplotype donors for patients with AML. Figure Figure

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