Take 2: Why Genetic Recombination Is Not Random, and How Cells Take Advantage of Non-randomness

08/07/2012 01:37 pm ET | Updated Oct 07, 2012
  • James A. Shapiro Author, 'Evolution: A View from the 21st Century'; Professor of Microbiology, University of Chicago

In the first comment on my last blog, Philip Rivera posted:

Unfortunately IMHO, your newer articles are still way too complex for the general public to grasp and the problem is that they are far less knowledgeable about evolution.


So keep it VERY simple ... [T]here is 100,000 potential average readers who need to learn from you! However, they should not have to be first versed in the Latin and Greek languages and have a science degree in order to grasp your theories!

Dr. Shapiro, you currently have arguably the most powerful message from science to the general public, but it is worthless if it is not understandable. Your detractors know this...

Since Philip's well-intentioned criticism was justified and constructive, I'll revisit the subject of genetic recombination differently so my main point is easier to understand. Readers who want to access experimental details can find appropriate links in the previous blog.

In the pre-DNA era, students were all taught that genetic change is random and accidental. Because the molecular details were inaccessible, this was the default assumption. But once we learned about DNA carrying hereditary information, we could research the details of how changes occur. We no longer needed to assume. We could investigate.

One of the main topics in molecular genetics has been the process of recombination between homologous chromosomes. This process makes it possible to construct genetic maps showing the relative positions of markers along the chromosomes.

Homologous recombination is not accidental. It is a required part of the special cell divisions called "meiosis" that that produce sperm and egg cells with only one copy of each chromosome. Without meiosis, sexual reproduction would not be possible as found today in higher organisms.

During recombination, chromosomes physically swap segments to generate new combinations of genetic loci without changing their order. Examining how frequently different combinations arise is the basis for computing genetic maps.

In the pre-DNA period, recombinational exchange was called "breakage and reunion." This physical swapping means that cells undergoing meiosis have to cut and splice the DNA molecules in their chromosomes. Molecular studies have revealed that at least a dozen proteins acting in sequence carry out such accurate cutting and splicing (one form of natural genetic engineering).

Recombinational exchange starts with breaks in DNA. When this occurs accidentally, it initiates a recombination process that repairs the break. This repair capacity may well be the original adaptive function of this sophisticated biochemical process.

But cells do not leave to chance what happens to their genomes. They use special DNA-cutting enzymes to initiate recombinational exchange. A University of Chicago colleage, Rochelle Esposito, discovered the enzyme used in meiosis. This enzyme prefers certain DNA sequences to cleave and creates so-called "hotspots" where recombination occurs most often. Sequence preference is one source of non-randomness in recombination.

We have recently learned that mouse cells exert control over recombinational hotspots in meiosis. They produce a blocking protein that binds to cleavage sites that coincide with highly evolved combinations of expression signals in the DNA. This inhibition protects those adaptive combinations from disruption by recombinational exchanges. As we often find in cell biology, one specificity leads to another so biochemical processes are tightly controlled against bad outcomes.

Not all recombinational exchanges occur at corresponding positions on homologous chromosomes. As DNA sequencing reveals, genomes are full of repeated segments at many different locations. Our own genomes contain over 40 percent of their DNA as dispersed repeats.

Recombination between repeats at different locations leads to chromosome rearrangements. Because the locations of the repeats determine where the rearrangements occur, this is another non-random feature of recombinational exchange.

Different organisms take advantage of both sources of non-randomness to target recombinational exchange for functional goals. Cells transfer different DNA sequence information from one genomic location to another when the differences are surrounded by homologous repeats. The cells use specific cleavage at a repeat to initiate recombinational exchange.

The generic term for a sequence flanked by homologous repeats is "cassette." Cassette exchange serves a number of different adaptive purposes, illustrating how inherent non-randomness in natural genetic engineering can be used and reused.

In yeasts, cassette exchange functions to switch mating types -- in effect to perform a sex change. This benefits the yeast cells because it allows the progeny of a haploid spore with one copy of the genome to produce cells of opposite mating type, which can fuse to cells of the original mating type to form diploid cells with two copies of the genome. Being diploid is advantageous because it enables the cell to repair accidental DNA breaks by recombination.

In disease-causing microbes, both bacteria and eukaryotes, cassette exchange serves to alter the DNA encoding surface proteins. By regularly changing surface protein structures, these organisms can adapt to new niches in their hosts and evade immune system defenses. The tenacity of illnesses like Lyme disease and sleeping sickness is a direct result of the causative microbes escaping immune surveillance through cassette exchange.

In chickens, the immune system itself uses recombinational cassette exchanges to diversify antibody structure. This diversification is essential to producing antibodies that can recognize an unpredictable variety of invaders.

In this blog, we have seen some functional advantages of non-random natural genetic engineering by homologous recombination. The benefits extend from disease-causing bacteria through sex-changing yeasts to disease-fighting chickens. Uncovering these examples is just one result of the tremendous scientific transition in which we have advanced from treating hereditary mechanisms as a black box to examining DNA-based inheritance in precise molecular terms.

I hope Philip Rivera will let me know if this version of the story satisfactorily responds to his critique.