Microcephaly: tracing the evolutionary lineage of ASPM gene

ABSTRACT

Microcephaly, in the form of congenital autosomal recessive disorder [MCPH], is characterized by the reduced occipital frontal head circumference >3 standard deviation of otherwise normal population of matching age and sex. The disease is primarily associated with mild to severe mental retardation. Earlier studies have unravelled that among Pakistani population, mutations in ASPM gene is strongly associated in MCPH. In the present study, we have explored the ancestral root of this disease and the process involved in its evolution using tools of bioinformatics. Experimental Methods: cDNA gene and protein sequences of ASPM gene were retrieved from NCBI database and subjected to the non-redundant BLAST. Consensus phylogenetic tree was developed after multiple sequence alignment and bootstrapping of the protein sequences of ASPM gene from different mammals using Neighbour Joining method, selecting non mammals as an out group. Comparisons of the gene synteny and exon and intron patterns of ASPM gene were also undertaken to investigate chromosomal changes during the course of human evolution. Different statistical evolutionary models namely, Codon Based Z test and Maximum Composite Likelihood Estimate were used in order to estimate the nature of nucleotide substitution and the type of selection pressure the gene has undergone. Phylogenetic tree based on ASPM gene clearly segregated all non mammalian members as an out group. Mammalian in group holds the established evolutionary lineage, based on morpho-genetic attributes of mammalian evolution, segregating monotremes at the beginning followed by the members of rodentia and finally radiation of the primates including humans. Orientation of the ASPM gene remains conserved between human and chimpanzee, however, it was found reversed along with two flanking genes, a zinc finger binding domain 41 and coagulation factor XIII, which suggest relatively recent event of gene inversion. Some earlier and, in comparison, more intricate chromosomal changes have also been detected among the lower order of mammals. Aligning ASPM gene exons with the primates and lower order mammals indicates transitional bias of mutation over transversion [R value= 1.563]. Holistically, codon based Z test revealed positive selection pressure on of ASPM gene from rodentia to primates. Briefly, the studies highlights the evolutionary events of ASPM gene in mammals especially primates including humans. Further studies in connection to correlating the cranial cavity size and ancestral gene sequences and in depth sequence comparison would be more insightful in this regard and studies in this connection are ongoing and will be reported shortly