In these GEITP email blogs, we have often discussed genes that are a member of this or that “gene family,” and we know that members of a gene family generally arise from the original ancestral gene. But, going back further in evolution, how did Mother Nature create the original gene, in the first place — which then led ultimately to a family of homologous genes in that species? [Recall that an “ortholog” is a gene that has evolved from a common ancestral gene by speciation (and usually has retained a similar function in different species). “Paralogs” are genes related by duplication within the genome (and often they have acquired a new function). “Analogs” are distinct (not usually related) genes that share the same or similar function, but which have arisen by convergent evolution. ”Homologs” (a generic term) are genes that share the same origin. Thus, orthologs and paralogs are homologs whereas analogs are not.]
One of our most favorite examples of convergent evolution is the “creation of a much-needed antifreeze glycoprotein gene (AFGP),” when it became a necessity for survival of a species. The Antarctic notothenioid fish Dissostichus mawsoni AFGP gene arose from a pancreas-derived (trypsinogen) gene and evolved into a protein segment with 41 triplet repeats. This gene arose between 5 and 14 million years ago (MYA), correlating with the estimated time (~10-14 MYA) when the Antarctic Ocean froze over; thus, evolutionary environmental pressure (freezing water conditions) resulted in formation of an antifreeze protein to preserve survival of this fish species.
In the Arctic Ocean, glaciation is estimated to have occurred ~2.5 MYA. Using cloning tricks, scientists found an AFGP gene in the Arctic cod Boreogadus saida (by using the Antarctic AFGP repeat “Thr-Ala-Ala” as a probe). This AFGP protein was found to be derived from a totally different gene, and originated around the time (~2.5 MYA) at which the Arctic Ocean is estimated to have frozen over…!! So, here we have two different fish species, each living at their own pole of the planet — needing a protein (at different evolutionary times) in response to the emergence of a cold environment. This is a beautiful example of convergent evolution.
The phenomenon of de novo gene birth — i.e., emergence of genes from non-genic sequences — has received considerable attention, due to the widespread occurrence of genes that are unique to particular species or genomes. Most instances of de novo gene birth have been recognized through comparative analyses of genome sequences in eukaryotes (organisms having paired chromosomes), despite the abundance of novel, lineage-specific genes in bacteria (prokaryotes having single unpaired chromosomes) and the relative ease with which bacteria can be studied in an experimental context.
The Long-Term Evolution Experiment (LTEE) with Escherichia coli (E. coli) is a microbial evolution study that began in 1988 and continues today. Located at University of Texas (Austin), the experiment was initiated and is still being overseen by Jeffrey E. Barrick. The study involves 12 populations of E. coli that are descendants of the same ancestral strain and have been evolving in a controlled environment for over 75,000 generations (in human generation-times, this would require more than 1.5 million years).
Authors [see attached pdf] explored the genetic record of the E coli long-term evolution experiment (LTEE) for changes indicative of “proto-genic” phases of new gene birth in which non-genic sequences evolve stable transcription and/or translation. Over the time span of the LTEE, non-genic regions were found to be frequently transcribed, translated, and differentially expressed, with levels of transcription across low-expressed regions — increasing in later generations of the experiment.
Proto-genes that were formed downstream of new mutations resulted either from insertion element activity, or from chromosomal translocations that fused preexisting regulatory sequences to regions that were not expressed in the LTEE ancestor. In addition, authors identified instances of proto-gene emergence in which a previously unexpressed sequence was transcribed after a new formation of an upstream promoter (although such cases were rare, when compared to those caused by recruitment of preexisting promoters). Tracing the origin of the causative mutations, authors discovered that most occurred early in the history of the LTEE, often within the first 20,000 generations, and became fixed soon after emergence. These data show that [a] proto-genes emerge frequently within evolving populations, [b] can persist stably, and [c] can serve as potential substrates for new gene formation.
DwN
PLoS Biol May 2024; 22: e3002418
COMMENTS:
Dan,
Really nice article! But let’s remember that there are no pressures on the genome by need. New genes are born by random changes in the genome — which happen to lead to survival of the fittest…
Reply,
EXACTLY. Random changes in genomes are constantly occurring over millions-of-years — until the stochastic process leads to an advantageous event that in some way improves survival of the species…
This is a very difficult concept for most people (including many scientists) to comprehend. When time is virtually infinite, a beneficial series of mutations eventually happens — leading to a new gene whose gene product helps the organism evolve more successfully (improvement in finding food, avoiding predators, and/or reproduction). Charles Darwin had it right.
—DwN
Dan,
So, apparently random changes that do not benefit the organism lead to extinction. Right?
Reply,
Ray,
No, it’s not that simple. First, the vast number of nucleotide changes (mutations, variants) in an organism’s genome have no effect; either they’re in a noncoding region of the gene, or the change does not elicit any amino acid change, or the new variant changing an amino acid is neutral (i.e., either no benefit or no detriment to survival). These “no-effect” mutations will eventually be lost over millions of years and many generations. “Extinction” of a species is not directly related to these no-effect or detrimental-effect nucleotide changes; rather, extinction of a species is more closely related to environmental pressures (e.g., geographical changes in cold or warmth as a function of time) leading to all members of the species not able to survive and/or reproduce.
A related question might be “How many de novo mutations exist in an offspring that is not seen in either parent?” Obviously, this number will vary widely among species, depending on genome size, generation time, etc. For humans, at birth, children typically have 70 (with a range of 10 to 300) new genetic variants, compared to their parents (out of the 6 billion letters that make both parental copies of DNA sequence). An important 2019 study published in eLife shows that the number varies dramatically — with some newborns having twice as many mutations as others; characteristically, this runs in families.
These new insights were found by performing whole-genome sequencing (WGS) and genetic analysis on 603 individuals from 33 three-generation families from Utah, the largest study of its kind. The families were part of the Centre d’Etude du Polymorphisme Humain (CEPH) consortium that are central to many key investigations that has formed a modern understanding of human genetics. The large size of the Utah CEPH families, which had as many as 16 children over a span of 27 years, made them well-suited for this new investigation.
This difference in new genetic variants is based largely on two influences. One is the age of a child’s parents. A child born to a father who is 35 years old will likely have more mutations than a sibling born to the same father at 25.
“The number of mutations we pass on to the next generation increases with parental age,” said Thomas Sasani, lead author of the study and a graduate student in human genetics at U of Utah Health Center. Previous studies have demonstrated the phenomenon, also confirmed by this study.
A second difference in number of new genetic variants is genetics. The effects of parental age on mutation rates differ dramatically among families — much more than had been previously appreciated. Within one family, a child may have two additional mutations compared to a sibling born when their parents were ten years younger. In another family, two siblings born ten years apart to a different set of parents may vary by more than 30 mutations.
“This shows that we as parents are not all equal in this regard,” said Aaron Quinlan, PhD, senior author of the study, and Professor of Human Genetics at U of Utah Health, and Associate Director of the Utah Center for Genetic Discovery. “Some of us pass on more mutations than others and this is an important source of genetic novelty and genetic disease.”
Impacts of new mutations depend on where they land in our DNA, and on the passage of time. On rare occasions, the genetic changes cause serious disease, but the majority occur in parts of our genetic code that don’t have obvious effects on human health.
And even though these new changes make up a small fraction of the overall DNA sequence, they add up with each subsequent generation. Increasing the so-called mutation load could potentially make individuals more susceptible to illness, said Sasani. It remains to be determined whether factors that impact the mutation rate increase the likelihood for certain diseases.
Although the majority of new mutations originally arise in fathers’ sperm, not all do. One in five mutations come from mothers’ eggs, and increasing age does not drive as many new mutations in mother as it does in fathers. Further, as mentioned above, the ~70 new mutations seen in children come from neither parent. Instead, they arise anew in the embryo (during embryogenesis) soon after fertilization.
DwN
COMMENT
Is there a relationship between the taxonomic and the genic terms “family”?
Reply,
Alvaro — The short answer is “no.” The longer answer is — what has been called “gene superfamily” since the 1980s is a term now frowned upon. “Gene family” is now preferred, which refers to all homologous genes unequivocally derived from one ancestral gene. For example, a family member can exist in virus or bacteria, as well as human (e.g., CYP the cytochrome P450 family), we can conclude the ancestral gene existed more than ~3.8 billion years ago.
If the first homeobox (Hox) gene evolutionarily first appeared in Cnidaria (e.g., jellyfish) before the earliest Bilatera (this would make them pre-Paleozoic), we can assume members of that gene family will exist in all descendants of Cnidaria evolution, which is estimated to have arisen evolutionarily ~1,000 million years ago.
If a gene evolutionarily first appeared in yeast [e.g., Nat Commun 12, 604],” we can safely assume members of that gene family will exist in virtually all descendants of yeast evolution, which is estimated to have arisen evolutionarily during the Cretaceous period, around 145 million years ago — (unless the gene was unimportant in some downstream species and therefore was lost).
In conclusion, there is no relationship between the taxonomic and gene germs “family.”
COMMENTS:
Paul, you are absolutely correct. The main topic of this email chain has dealt (so far) only with “pure” mutational changes during evolution. However, numerous “environmental pressures” can markedly “speed up” evolutionary changes — if the alternative choice is possible extinction of the species. For example, the finches (living on the various isolated Galapagos Islands) needed to change their bill size and shape in less than 2 million years, in order to accommodate different foods (e.g., type of seeds from evergreen trees) as their only dietary source for survival. There is some evidence that finches were able to begin measurable beak changes in two generations.
Another example is the Atlantic killifish, Fundulus heteroclitus, an abundant fish broadly distributed in estuaries along the northeastern coast of the U.S. Known for their hardiness to industrial pollution, populations of killifish have repeatedly been shown to rapidly evolve tolerance to levels of aromatic hydrocarbon (i.e., polycyclic hydrocarbons, polyhalogenated biphenyls, dioxins) exposure that would otherwise be lethal. This tolerance, which is heritable (passed on to their offspring), has been found to be associated with decreased activation of the aryl hydrocarbon receptor (AHR) signaling pathway.
Other examples would be bacteria becoming resistant to an antibiotic and cancer cells becoming resistant to chemotherapeutic drugs. In both cases, the “subject” senses an environmental pressure that can be lethal — if “the subject” (bacteria, cancer cells) cannot mutate rapidly the necessary genes to develop antibiotic resistance and tumor resistance, respectively. There is a vast literature on this topic, which (among several terms) has been called “molecular drive”
Hello Dan
Professor Lancet reminds us that there is no pressure on the genome due to need, but surely this fish, Dissostichus mawsoni, had a crucial need — if it was going to survive, as the Arctic Ocean began to freeze over. Similarly, the different bill morphology of the Galapagos Island finches would have also needed to happen in a relatively short time. Limitless time was not available to them.
The mutations that permitted survival (of the Arctic fish, the Galapagos finch) had only a few generations’ leeway to occur and become established in the species. I am way out of my depth in terms of genetics science, but Darwinian observations tell me that some environmental drivers can influence the direction of vital mutations beyond just random events that have all eternity to manifest. I thought that this hypothesis was already well accepted.
PS, MD, Retired physician, London, UK
COMMENT:
Doron, I have followed this topic with interest — since the early papers of Carl Woese, Otto Kandler and Mark Wheelis in the 1970s and 80s. The Last Universal Common Ancestor (LUCA), is the prokaryote-like organism that is the assumed ancestor of all living things on Earth. To get everyone on the same page, planet Earth is estimated to have formed ~4.54 billion years ago (BYA). There are two schools of thought as to when LUCA arose during evolution.
One, LUCA is thought to have lived between 3.8 and 3.5 BYA, meaning that it would have emerged around the time the three domains of life (Archaea, Eubacteria, and Eukarya) came into being. [Archaea (Archaebacteria) are single-celled microorganisms (most likely the oldest and therefore closest to LUCA) that can live in extreme environments (i.e., hot temperatures, high pH levels, low temperatures, or salty environments). Archaea have some features of both Eubacteria and Eukarya (i.e., no nucleus to house their single chromosomes of DNA, and a similar structure to Eubacteria). Eubacteria are single-celled microorganisms that also have no nucleus to contain their single chromosome of DNA. Eukarya are the more complex organisms — whose cells almost always have a nucleus, paired chromosomes inside that nucleus, and other membrane-bound organelles — which have given rise to protists, plants, fungi and animals.]
Number two (the more recent school of thought) is that some researchers now estimate LUCA lived closer to Earth’s formation (~4.5 BYA), based on improved methods of analysis. LUCA is thus proposed to have appeared in the 4.2 BYA to 3.8 BYA time period; by 4.2 BYA, some regions of Earth were postulated to be sufficiently hospitable for “earliest life forms” to exist. Thus, going from Prof. Lancet’s proposed primitive micellar or vesicular protocells to the earliest functional prokaryote — might have taken place over a period of perhaps ~400 million years.
At present, the oldest factual evidence of life on the planet is found in 3.48-billion-year-old rocks in Western Australia. This material is said to show remnants of stromatolites — “mounds of sediment formed of mineral grains glued together by ancient bacteria.” These oldest known fossils of life on Earth are proposed to have been formed by cyanobacteria, living in the Dresser Formation in Western Australia. These fossils are believed to have arisen from “photosynthetic organisms that lived in shallow lagoons fed by nutrient-rich water.”
DwN
From: Doron Lancet
Sent: Thursday, July 11, 2024 11:27 AM
Dan, returning to your email to me on July 10 in this long email-chain, I support every word! “When time is virtually infinite, a beneficial series of mutations eventually happens — leading to a new gene whose gene product helps the organism evolve more successfully (improvement in finding food, avoiding predators, and/or reproduction).” Most people cannot comprehend how random mutations — occurring over millions of years — can eventually result in an ordered molecule with a function that helps the organism. And pointing out the incredibly slow pace of (advantageous) mutations eventually appearing; hence evolution, is truly important.
It is this pace that allows a primitive micellar or vesicular protocell to reach the “last universal common ancestor” (LUCA), which would likely have to be as complex as a present-day modest bacterium. In simple terms, it may well have taken more than 500 million years — as long as the time it has taken to evolve from early multicellular organisms to Homo sapiens. See our attached abstract (presented at a meeting at Georgia Tech last March).
By the way — what is your opinion on “who and when exactly did the first true multicellular organism arise?”
Doron