RT Journal Article
SR Electronic
T1 Ankyrin-1 gene exhibits allelic heterogeneity in conferring protection against malaria
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 114959
DO 10.1101/114959
A1 Hong Ming Huang
A1 Denis C. Bauer
A1 Patrick M. Lelliott
A1 Matthew W. A. Dixon
A1 Leann Tilley
A1 Brendan J. McMorran
A1 Simon J. Foote
A1 Gaetan Burgio
YR 2017
UL http://biorxiv.org/content/early/2017/03/08/114959.abstract
AB Allelic heterogeneity is a common phenomenon where a gene exhibit different phenotype depending on the nature of genetic mutations. In the context of genes affecting malaria susceptibility, it allowed us to explore and understand the intricate host-parasite interactions during malaria infections. In this study, we described a gene encoding erythrocytic ankyrin-1 (Ank-1) which exhibit allelic heterogeneity during malaria infections. We employed ENU mutagenesis screen on mice and identified two Ank-1 mutations, one resulted in an amino acid substitution (MRI95845), and the other a truncated Ank-1 protein (MRI96570). Both mutations caused hereditary spherocytosis-like phenotypes and confer protection against Plasmodium chabaudi infections. Upon further examination, Ank-1(MRI96570) mutation was found to inhibit intra-erythrocytic parasite maturation, whereas Ank-1(MRI95845) caused increased bystander erythrocyte clearance during infection. This is the first description of allelic heterogeneity in ankyrin-1 from the direct comparison between two Ank-1 mutations. Despite the lack of direct evidence from population studies, this observation further supported the protective roles of ankyrin-1 mutations in conferring malaria protection. This study also emphasised the importance of such phenomenon to achieve a better understanding of host-parasite interactions, which could be the basis of future studies.Authors' summary In malaria endemic regions, many individual developed natural resistance against the disease by having certain genetic mutations that affect the ability of malarial parasites to survive within the human body, notably the red blood cells. However, it is often observed that different mutations within the same gene could give rise to different degree of malaria protection. Through studying this phenomenon, we are able to better understand the underlying cause of their protective effects. In this report, we study two mutations of ankyrin-1 gene, MRI96570 and MRI95845, both of which protect mice from malaria infections. However, both of them exhibit stark differences in the way they mediate protection. MRI96570 affects the ability of malarial parasites to develop inside the red blood cells, whereas MRI95845 enhances the destruction of red blood cells during malaria infection. This is the first direct observation of two distinct methods of achieving malaria protection from ankyrin-1 gene. This report also highlights the complex relationship between the human and malarial parasites, and that such phenomenon might be more common than we initially expected.