by Patricia Babin
As a scientist and a female in a male-dominated profession, I tend to like science-fiction, action-adventure, and crime movies a little more than most of my female friends, but I still enjoy an occasional chick flick. One of my favorites is Sleepless in Seattle. There’s a scene in the movie where young Jonah (Ross Malinger) decides he needs get to the Empire State Building to meet his favorite candidate for a new mom. Jonah asks his friend how much a ticket to New York costs. She replies, “Nobody knows. It changes practically every day.”
Here’s another question for which the best answer is “nobody knows”: “What percentage of single nucleotide changes (point mutations) are extremely harmful or lethal?” Though biologists seem to agree that most mutations are either harmful or neutral, there aren’t many studies that address this question directly. Yet it is an important issue since mutations are the biological mechanism through which Darwinian evolution is proposed to occur. It also carries implications for the argument that humans are unique from other advanced life.
In a previous Today’s New Reason to Believe, I stated that scientists were discovering that the biological basis for human uniqueness is far more subtle than scientists had envisioned initially. Some people mistakenly believe that my reference to “subtle mechanisms” gives credibility to evolution. They think that admitting that small changes can make big differences gives ground to the evolutionary paradigm—but it doesn’t. Changes, if not the correct ones, can be deadly.
In some cases, the mutation is fatal prior to birth; in other cases, the mutation greatly shortens the organism’s life span. There are probably a significant number of point mutations fatal to an organism—yet we don’t investigate these occurrences unless the species is (1) one we value highly—like humans—or (2) is relevant for research purposes. So, the only fatal point mutations we are generally aware of fall into these categories even within these limitations, fatal point mutations still occur in significant numbers. Here are a few examples from the scientific literature published just in the past year (gene names are italicized, protein names are not):
- A point mutation in the IKAROS gene—the gene responsible for the differentiation of lymphocytes—results in a single amino acid substitution in the DNA-binding domain of the IKAROS protein and causes congenital pancytopenia, a rare and generally lethal blood disease.1
- A point mutation in the SCN4A gene that changes an alanine amino acid to a serine amino acid produces a lethal muscle condition in infants.2
- A point mutation in the CHUK gene results in a lethal syndrome in human fetuses in which there are multiple malformations, including face malformations and a lack of limbs.3
But not all mutations are created equal. The story of the human FOXP2 gene clearly demonstrates that the right changes can be extremely beneficial, while the wrong changes in the very same gene can cause severe problems. This example adds impetus to the idea that changes need to be carefully designed, rather than random, to generate positive outcomes.
Beginning in the early 1990s, geneticists studied a family (identified only as KE) that exhibited a severe hereditary speech and language disorder over three generations.4 The symptoms experienced were intense: the inability to control the fine movements of the orofacial muscles necessary for articulation, the inability to break up words into their constituent sounds, and a lack of basic grammatical skills.5 After many years of work, the mutation responsible for the disorder was identified as a single nucleotide change from G to A in the protein coding region of FOXP2.6
The FOXP2 protein is a transcriptional regulator, meaning it exerts its effect by binding to DNA and causing either a decrease or an increase in transcription. This particular nucleotide change results in the substitution of an arginine amino acid for a histidine amino acid in the FOXP2 protein. Scientists hypothesize that the mutation in the FOXP2 gene and the resulting change in its protein sequence affects the ability of the protein to bind to DNA correctly. Mice carrying this mutant version of FOXP2 display lung and brain defects, low weight, and die within a few weeks of birth.7
Several years later, scientists realized that among all species, humans alone carry a unique version of FOXP2 that is foundational to humanity’s advanced written and spoken language abilities. The human FOXP2 differs from the chimp FOXP2 by two nucleotides and from the mouse FOXP2 by three.8 The two nucleotide changes in the human FOXP2 result in two amino acid changes in its protein. Those changes dramatically alter the DNA binding activity of FOXP2. These alternations are essential to the humanity’s extraordinary language capabilities. Specifically, human FOXP2 up-regulates 61 genes and down-regulates 55 genes when compared to the chimp version of FOXP2.9
Clearly, not all changes are “created equal.” Small changes can have enormous consequences either for the good or for the bad. The mutation seen in the KE family was only a single nucleotide change in DNA and a resulting single amino acid change in its protein sequence with devastating results. The two nucleotide changes seen in the normal human FOXP2 and its accompanying two amino acid changes in protein sequence have dramatic beneficial results. It’s all about the right changes.
- Frederick D. Goldman et al., “Congenital Pancytopenia and Absence of B Lymphocytes in a Neonate with a Mutation in the Ikaros Gene,” Pediatric Blood Cancer (May 5, 2011): doi: 10.1002/pbc.23160. [Epub ahead of print].
- Dina Simkin et al., “Mechanisms Underlying a Life-Threatening Skeletal Muscle Na+ Channel Disorder,” Journal of Physiology (April 26, 2011). [Epub ahead of print]
- Jenni Lahtela et al., “Mutant CHUK and Severe Fetal Encasement Malformation,” New England Journal of Medicine 363 (October 21, 2010): 1631–37.
- Jane A. Hurst et al., “An Extended Family with a Dominantly Inherited Speech Disorder,” Developmental Medicine and Child Neurology 32 (April 1990): 352–55; Simon E. Fisher et al., “Localisation of a Gene Implicated in a Severe Speech and Language Disorder,” Nature Genetics 18 (February 1998): 168–70; M. Gopnik and M. B. Crago, “Familial Aggregation of a Developmental Language Disorder,” Cognition 39 (April 1991): 1–50; Faraneh Vargha-Khadem et al., “Praxic and Nonverbal Cognitive Deficits in a Large Family with a Genetically Transmitted Speech and Language Disorder,” Proceedings of the National Academy of Sciences, USA 92 (January 31, 1995): 930–33. Faraneh Vargha-Khadem et al., “Neural Basis of an Inherited Speech and Language Disorder,” Proceedings of the National Academy of Sciences, USA 95 (October 31, 1998): 12695–700.
- Cecilia S. Lai, “A Forkhead-Domain Gene is Mutated in a Severe Speech and Language Disorder,” Nature 413 (October 4, 2001): 519–23.
- Matthias Groszer et al., “Impaired Synaptic Plasticity and Motor Learning in Mice with a Point Mutation Implicated in Human Speech Deficits,” Current Biology 18 (March 11, 2008): 354–62.
- Genevieve Konopka et al., “Human-Specific Transcriptional Regulation of CNS Development Genes by FOXP2,” Nature 462 (November 12, 2009): 213–17.