Are mutations random?

According to James Shapiro (2011, Evolution: A View from the 21st Century, p. 82):

There is one last area where the traditional assumptions about genetic change have been shown to be unrealistically restrictive. That is the question of targeting changes to specific regions in the genome. Conventional wisdom and the vast majority of evolutionists assert that there is no way natural genetic engineering functions can "choose" where to operate within the genome. This was a topic of active debate in 1988 when some adaptive mutation experiments were initially overinterpreted in neo-Lamarckian terms [2, 669, 670].

Despite interpretive errors in the Lamarck vs. Darwin debate, a priori denials of the capacity for functional targeting of biochemical changes to DNA should be jarring to molecular biologists. We have over 50 years of investigation into the molecular basis of how cells regulate transcription, and all biologists agree that the transcription apparatus can be directed to specific, functionally appropriate sites in the genome. The reason for the denial in the case of mutation probably has to do with a continuing influence of the late 19th Century philosophical notion that "germ plasm" inheritance has to be isolated from the soma [671]. But in the 21st Century, when we know about transcriptional regulation, signal transduction from the cell surface to the genome, and the operation of natural genetic engineering in the germline, it is time to abandon this mistaken doctrine.

It is difficult (if not impossible) to find a genome change operator that is truly random in its action within the DNA of the cell where it works. All careful studies of mutagenesis find statistically significant nonrandom patterns of change [emphasis mine], and genome sequence studies confirm distinct biases in location of different mobile genetic elements. These biases can sometimes be extreme, as in the targeting of S. cerevisiae LTR retrotransposon insertions into regions just a few base pairs upstream of RNA polymerase III transcription start sites [672–674]. In many cases, we have some understanding of the molecular mechanisms and/or functional significance of the observed preferences (see Table II.11).

References

2. Sniegowski, P.D. and Lenski, R.E. Mutation and adaptation: The directed mutation controversy in evolutionary perspective. Annu Rev Ecol Systematics 26, 553-578 (1995).

669. Cairns, J., Overbaugh, J. and Miller, S. The origin of mutants. Nature 335, 142-5 (1988).

670. Maenhaut-Michel, G. and Shapiro, J.A. The roles of starvation and selective substrates in the emergence of araB-lacZ fusion clones. Embo J 13, 5229-39.

671. Weismann, A. The Germ-Plasm: A Theory of Heredity, (Charles Scribner's Sons, New York, 1893) (1994).

672. Bushman, F.D. Targeting survival: integration site selection by retroviruses and LTR-retrotransposons. Cell 115, 135-8 (2003).

673. Devine, S.E. and Boeke, J.D. Integration of the yeast retrotransposon Ty1 is targeted to regions upstream of genes transcribed by RNA polymerase III. Genes Dev 10, 620-33 (1996).

674. Bolton, E.C. and Boeke, J.D. Transcriptional interactions between yeast tRNA genes, flanking genes and Ty elements: a genomic point of view. Genome Res 13, 254-63 (2003).