Maximum-likelihood estimation of site-specific mutation rates in human mitochondrial DNA from partial phylogenetic classification

Abstract

The mitochondrial DNA hypervariable segment I (HVS-I) is widely used in studies of human evolutionary genetics, and therefore accurate estimates of mutation rates among nucleotide sites in this region are essential. We have developed a novel maximum-likelihood methodology for estimating site-specific mutation rates from partial phylogenetic information, such as haplogroup association. The resulting estimation problem is a generalized linear model, with a nonstandard link function. We develop inference and bias correction tools for our estimates and a hypothesis-testing approach for site independence. We demonstrate our methodology using 16,609 HVS-I samples from the Genographic Project. Our results suggest that mutation rates among nucleotide sites in HVS-I are highly variable. The 16,400-16,500 region exhibits significantly lower rates compared to other regions, suggesting potential functional constraints. Several loci identified in the literature as possible termination-associated sequences (TAS) do not yield statistically slower rates than the rest of HVS-I, casting doubt on their functional importance. Our tests do not reject the null hypothesis of independent mutation rates among nucleotide sites, supporting the use of site-independence assumption for analyzing HVS-I. Potential extensions of our methodology include its application to estimation of mutation rates in other genetic regions, like Y chromosome short tandem repeats.

Figure 1.—

(A) Schematic of the Hg view of a phylogenetic tree and (B) the full phylogenetic tree, including the internal Hg phylogenies, which we assume we do not observe.

Figure 2.—

Demonstration of our reasoning, that we know whether any mutations have occurred in a specific site.

Figure 3.—

The poly-C stretch. Position 16,189 is highlighted and five sequences are shown. A sequence identical to the rCRS in the presented region is shown at the top. Below it, four sequences containing the T16,189C polymorphism are arranged to show one to four adenosines preceding the poly-C stretch. A typical chromatogram of the sequence after the poly-C stretch is also demonstrated.

Figure 4.—

Graphical representation of mutation rates along HVS-I.

Figure 5.—

Smoothed bias estimation curves for our various estimation protocols, using our simulation–bootstrap hybrid. The smoothing was done using LOESS (Cleveland et al. 1992).

Figure 5.—

Smoothed bias estimation curves for our various estimation protocols, using our simulation–bootstrap hybrid. The smoothing was done using LOESS (Cleveland et al. 1992).

Figure 5.—

Smoothed bias estimation curves for our various estimation protocols, using our simulation–bootstrap hybrid. The smoothing was done using LOESS (Cleveland et al. 1992).

Figure 5.—

Smoothed bias estimation curves for our various estimation protocols, using our simulation–bootstrap hybrid. The smoothing was done using LOESS (Cleveland et al. 1992).

Figure 6.—

Comparison of the estimates (black circles) and confidence intervals from two of our variants and Bandelt et al. (2006). Note that the y-axis is on a logarithmic scale.