Suzuki and Nei (2002) propose an alternative, more heuristic method of estimation to counteract the problem of differing rates of substitution before and after zoonotic events. By either assuming that a single rate of nucleotide substitution holds for the region preceding the common ancestor of each subtype or by smoothing the rate of nucleotide substitution over clades with different numbers of taxa, the adherence to a MCA prevents direct inference of the rate during subtype divergence. In considering divergence events between viral subtypes, even when the MCA well-approximates nucleotide substitution within a given subtype, the above methods may incorrectly infer the time of divergence across subtypes. influenza A-H3N2 in human hosts, as in ) or deviates from the MCA homogenously in time (e.g. Consequently, these methods provide inference most suitable for situations where sequence evolution follows a MCA (e.g. Committed to some variant of the MCA, current algorithms then estimate the rate of nucleotide substitution over all taxa in a given set. Looser forms of MCAs require only that the proportionality hold along individual branches, with the rates across branches drawn from a pre-specified distribution. In its strict formulation, the MCA posits a proportional relation between the number of substitutions and the intervening time period over the entire phylogeny. The most commonly employed approach determines the divergence time of subtypes using a molecular clock assumption (MCA) over an entire phylogeny. Two primary methods find use to date the time of viral subtype divergence. Consequently, studies of the date of origins of viral subtypes must use strong a priori assumptions on the rate structure of nucleotide substitution. Unfortunately, no studies thus far analyze the rate of nucleotide substitution during either geographical invasion or zoonosis. In Dengue, where a single subtype simultaneously inhabits two hosts (humans and Aedes aegypti) in a persistent zoonotic process, the introduction of the virus to new geographical environments associates with a dramatic increase in sequence diversity. For the last three viruses, a unique zoonotic transfer appears to co-occur with substantial changes in both the composition of nucleotides and amino acids as well as alterations in the rate of nucleotide substitution. Systematic studies characterize the substitution process and substitution rate process of several classes of viral subtypes in, for example, Dengue, influenza subtype A, human immunodeficiency virus (HIV) and the virus responsible for sudden acute respiratory syndrome (SARS). Further, the recent availability of viral gene sequences sampled at a pace commensurate with their rate of nucleotide substitution vastly augments the ability to rigorously infer the time scale of phylogenies and hence determine the time of the most recent common ancestor (TMRCA) for different viral types. For example, archeological sequence data can furnish accurate dates and show that substantial genomic changes associate with geographical invasion and zoonosis. Improved estimates equip epidemiologists and virologists to begin to correlate these important establishing events with historical demographic changes, geographical invasions and zoonoses, the transferring of a virus from one host species to another. Precise estimates are sorely lacking for dating the emergence and divergence of viral subtypes. We show a time of divergence approximately 100 years ago, substantially more recent than previous estimates which range from 250 to 3800 years ago. As an example, we calculate the time of divergence for three genes among influenza subtypes A-H3N2 and B using subtype C as an outgroup. We accomplish this by blending estimates of the substitution rate for triplets of dated sequences where each sequence draws from a distinct viral subtype, providing a zeroth-order approximation for the rate between subtypes. As the underlying structure of the substitution rate process at the time of subtype divergence is not understood and likely highly variable, we present a simple method that estimates rates of substitution, and from there, times of divergence, without use of an assumed molecular clock.
Currently, researchers use two strategies to approach this task, both requiring strong conditions on the molecular clock assumption of substitution rate.
When historical data are absent (that is, the overwhelming majority), viral sequence sampling on a time scale commensurate with the rate of substitution permits the inference of the times of subtype divergence. Precise dating of viral subtype divergence enables researchers to correlate divergence with geographic and demographic occurrences.
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