Genome sequencing hides chromosome rearrangments -- which may be clinically very important.
In this age of genome sequencing, we can lose sight of the importance of how our genomes are distributed over 23 pairs of chromosomes. Rearrangements of the pairs are invisible to sequencing, because the correct amount of genetic material is present.
A recent genetic counseling session reminded me of a chromosomal quirk that flies completely under the radar of genome sequencing, yet if it turns up in two copies in a bunch of people who have sex, could actually begin a second human species, who have 22 pairs of chromosomes.
CHROMOSOME PIGGYBACKS
The young couple had suffered several early pregnancy losses, and tests revealed extra DNA from chromosome 22. Although 22 is tiny, the excess somehow ends development just as an embryo is becoming a fetus. The lab report profiled single nucleotide polymorphisms (SNPs), landmarks among the chromosomes, and detected overrepresentation of the chromosome, but called it a trisomy, as if it stood alone. It didn't. An old-fashioned karyotype (chromosome chart) would have shown the extra tiny chromosome glommed onto one of the other chromosomes. Only that rearrangement could explain the pregnancy losses.
One type of chromosome adhered to another is a Robertsonian translocation, named after William Rees Brebner Robertson, Ph.D., who first described it in 1916 in grasshoppers. The person, or grasshopper, with one piggybacked “Rob” chromosome is fine, because the correct two gene sets are there – just rearranged. But making gametes (sperm or egg) is problematical, because the Rob chromosome has a dual identity from its two parts, and won’t separate as chromosome pairs typically do during meiosis. It’s a little like a couple in a square dance who won’t pull apart when everyone else does.
Let’s say a chromosome #22 has attached to a chromosome #13 in a man. His sperm can get a normal 13 and a normal 22; just the piggybacked 13;22, or 4 “unbalanced” possibilities that contribute too much or too little of the implicated chromosomes. For a family, that means a 2/3 risk of unbalanced chromosomes for each pregnancy.
One in 1,000 people has one Rob chromosome– she or he is a heterozygote (carrier) for it. They’re healthy, but infertile or prone to spontaneous abortion. Robertsonian translocations happen only in chromosomes that have one long arm and one very tiny arm, called an acrocentric, or in telocentrics, which have only a long arm (but aren’t in humans). Our acrocentrics are chromosomes 13, 14, 15, 21, and 22. A Robertsonian translocation of chromosome 21 accounts for the rare cases of Down syndrome that are not due to a full trisomy (extra chromosome) and are much more likely to recur.
OF MICE AND MUNTJACS
Reports of Robertsonian translocation in the animal kingdom are sparse, but curiously mice are particularly adept at shuffling their chromosomes, with acrocentrics and telocentrics glomming into larger metacentrics.
The first departure from the common Mus musculus house mouse is reportedly from the Vikings in 600 AD. The “tobacco mouse” (Mus poschiavinus), initially described in 1869 from specimens trapped in a tobacco factory in Valle di Poschiavo, Switzerland, were notable for their big heads and small, dark bodies. They were later found in the Italian Alps and their distinctive set of 22 chromosomes discovered, 9 pairs of equal-armed metacentrics formed from the ancestral 40 telocentrics characteristic of the house mouse.
The dynamic chromosome count of mice likely reflects attractions of TTAGAGAG repeats at their tips, which are echoed, but in reverse, at their main constrictions, the centromeres. Such reverse repeats in chromosomes function like Velcro, mixing and matching their parts, creating at least 100 different “races” of mice that are, genetically speaking, actually distinct species because like can only successfully reproduce with like. Carriers of Rob chromosomes have problems with fertility, but if carriers mate, they’re fertile. The resulting types of chromosomally-defined mice are geographically fixed, because mice don’t travel much (unless they sneak onto ships).
Muntjacs are also prone to Robs. The ancestral Muntiacus reevesi has 46 chromosomes in both male and female, whereas the derived Muntiacus muntjac has just 6 chromosomes in the female, and 7 in the male. Chromosome banding reveals that the two Asian deer species have the same genes, but they’re splayed out differently among the chromosomes. Rams and cotton rats have “Rob” chromosomes too.
Big chromosomes shattering into smaller ones, although that seems energetically more favorable than formation of a Rob, is actually rarer. Such chromosomal fission has been reported only in cultured cells, a zebra family, and in the black rat of Mauritius. Chromosome fusion at the tip rather than the exposed centromeres is also rare, but distinguishes Asian river buffaloes from Malaysian swamp water buffaloes.
A NEW BREED OF HUMAN?
Far far rarer than Rob heterozygotes are homozygotes with two Robs, because they can only arise from inheriting one copy of the unusual chromosome from each parent – which typically means the parents are related and inherited the Rob from a shared ancestor, like a common great-grandparent. Cases of these Rob homozygotes, who have 44 chromosomes rather than the normal 46, are exceedingly rare:
• A 1984 report describes a family with 3 adult siblings who had 44 chromosomes, #s 13 and 14 combined.
• A 1988 report tells of 3 distantly-related families in Finland, also involving #s 13 and 14, whose Rob passed in carriers through at least 9 generations, appearing in at least one homozygote.
• A 1989 paper describes a Rob between #s14 and 21 in a homozygote whose carrier parents were related.
Most oft-cited is a case report from 2013 of a 25-year-old healthy Chinese man who has 44 chromosomes because each 14 joins a 15 – a combo not seen before. His parents, both translocation carriers, were first cousins. The Chinese man’s sperm carry 21 autosomes and an X or Y, and he should be fertile – but only with a woman who is similarly chromosomally endowed. Chances are he’ll never find her. But if he does …
FROM SCIENCE TO SCI-FI
The report on the Chinese man with 44 chromosomes ends with: “The aberration can provide material for evolution. … Long term isolation of a group of individuals who are homozygous for a particular Robertsonian translocation chromosome could theoretically lead to the establishment of a new human subspecies having a full genetic complement in 44 chromosomes.”
It might have happened before. Could the 48 chromosomes of a shared ancestor of humans and chimps have branched to yield our 46 chromosomes? Fusion of chimp chromosomes 12 and 13, according to banding patterns, might have generated our larger chromosome 2.
The idea of inheriting a double dose of a Robertsonian chromosome fueling human speciation isn’t new. I wrote about it in 2002 in The Scientist, wherein Lisa Schaffer, PhD, of “Paw Print Genomics” at Washington State University, Spokane, who studied Robs, speculated, "With 1 in 1,000 individuals carrying a Robertsonian translocation, the likelihood of two carriers getting together and both transmitting their translocation is 1 in 4 million--so they are out there, just phenotypically normal."
The possibility of a new human species with 44 chromosomes lends perspective to certain science fiction plots. It may explain the origin of the bluish ghoulish subterranean Morlocks who eat the sun-loving peaceful aboveground Eloi in H.G. Wells’ future world of The Time Machine, written in 1898. Or the cannibalistic screeching humanoid monsters, our descendants, that will take over the future world depicted in last summer’s Wayward Pines.
Neither H. G. Wells or Wayward Pines’ creator Blake Crouch evoked Robertsonian translocation as a plausible route to rapid human evolution (or devolution). But sci-fi author Greg Bear came very close in his marvelous 1999 and 2003 novels Darwin's Radio and Darwin's Children.
Bear imagines that a latent retrovirus awakened in the genomes of some women pregnant in 1999 shuffled the genomes of a new generation in ways that create cells with 52 chromosomes instead of 46, thereby instantly creating a group that can successfully mate only among themselves. You’ll have to read the books to learn how and why the “virus children” are superior. Forced into camps by the fearful majority, they establish their own culture, further separating the two types of people. It is a compelling depiction of reproductive isolation leading, presumably, to speciation, with an initial chromosomal event as the impetus.
I spoke to Bear back in 2004, again for The Scientist. A self-taught scientist with a soaring imagination, Bear said, "My secrets are few. I love biology. I have been researching it in constant reading since the early 1980s. I saw very clearly that DNA must be computational, a self-organizing, self-repairing system. In the early 90s, it became clear to me that modern evolutionary theory was incomplete. I set out to find all the out-of-the-way papers that I could to prove that nature was a network, from top to bottom." The Darwin series arose from those thoughts.
I’m not very good at writing fiction and am in awe of people like Bear who can, but if I could, I’d follow up on this theme of 44-chromosome people arising and staying hidden in plain sight among those smugly having their genomes sequenced. Could social media help which, after all, wasn’t around when the Time Machine or even Darwin’s Radio were written. Alas, Facebook’s Robertsonian Translocation Support Group, founded in 2011, only has 2 posts, the first of which evokes the Lord, probably turning off those seeking scientific information.
When I’m through with my next round of textbook revisions, maybe I’ll give fiction a shot.
(This post was first published at my DNA Science blog at Public Library of Science)
A recent genetic counseling session reminded me of a chromosomal quirk that flies completely under the radar of genome sequencing, yet if it turns up in two copies in a bunch of people who have sex, could actually begin a second human species, who have 22 pairs of chromosomes.
CHROMOSOME PIGGYBACKS
The young couple had suffered several early pregnancy losses, and tests revealed extra DNA from chromosome 22. Although 22 is tiny, the excess somehow ends development just as an embryo is becoming a fetus. The lab report profiled single nucleotide polymorphisms (SNPs), landmarks among the chromosomes, and detected overrepresentation of the chromosome, but called it a trisomy, as if it stood alone. It didn't. An old-fashioned karyotype (chromosome chart) would have shown the extra tiny chromosome glommed onto one of the other chromosomes. Only that rearrangement could explain the pregnancy losses.
One type of chromosome adhered to another is a Robertsonian translocation, named after William Rees Brebner Robertson, Ph.D., who first described it in 1916 in grasshoppers. The person, or grasshopper, with one piggybacked “Rob” chromosome is fine, because the correct two gene sets are there – just rearranged. But making gametes (sperm or egg) is problematical, because the Rob chromosome has a dual identity from its two parts, and won’t separate as chromosome pairs typically do during meiosis. It’s a little like a couple in a square dance who won’t pull apart when everyone else does.
Let’s say a chromosome #22 has attached to a chromosome #13 in a man. His sperm can get a normal 13 and a normal 22; just the piggybacked 13;22, or 4 “unbalanced” possibilities that contribute too much or too little of the implicated chromosomes. For a family, that means a 2/3 risk of unbalanced chromosomes for each pregnancy.
One in 1,000 people has one Rob chromosome– she or he is a heterozygote (carrier) for it. They’re healthy, but infertile or prone to spontaneous abortion. Robertsonian translocations happen only in chromosomes that have one long arm and one very tiny arm, called an acrocentric, or in telocentrics, which have only a long arm (but aren’t in humans). Our acrocentrics are chromosomes 13, 14, 15, 21, and 22. A Robertsonian translocation of chromosome 21 accounts for the rare cases of Down syndrome that are not due to a full trisomy (extra chromosome) and are much more likely to recur.
OF MICE AND MUNTJACS
Reports of Robertsonian translocation in the animal kingdom are sparse, but curiously mice are particularly adept at shuffling their chromosomes, with acrocentrics and telocentrics glomming into larger metacentrics.
The first departure from the common Mus musculus house mouse is reportedly from the Vikings in 600 AD. The “tobacco mouse” (Mus poschiavinus), initially described in 1869 from specimens trapped in a tobacco factory in Valle di Poschiavo, Switzerland, were notable for their big heads and small, dark bodies. They were later found in the Italian Alps and their distinctive set of 22 chromosomes discovered, 9 pairs of equal-armed metacentrics formed from the ancestral 40 telocentrics characteristic of the house mouse.
The dynamic chromosome count of mice likely reflects attractions of TTAGAGAG repeats at their tips, which are echoed, but in reverse, at their main constrictions, the centromeres. Such reverse repeats in chromosomes function like Velcro, mixing and matching their parts, creating at least 100 different “races” of mice that are, genetically speaking, actually distinct species because like can only successfully reproduce with like. Carriers of Rob chromosomes have problems with fertility, but if carriers mate, they’re fertile. The resulting types of chromosomally-defined mice are geographically fixed, because mice don’t travel much (unless they sneak onto ships).
Muntjacs are also prone to Robs. The ancestral Muntiacus reevesi has 46 chromosomes in both male and female, whereas the derived Muntiacus muntjac has just 6 chromosomes in the female, and 7 in the male. Chromosome banding reveals that the two Asian deer species have the same genes, but they’re splayed out differently among the chromosomes. Rams and cotton rats have “Rob” chromosomes too.
Big chromosomes shattering into smaller ones, although that seems energetically more favorable than formation of a Rob, is actually rarer. Such chromosomal fission has been reported only in cultured cells, a zebra family, and in the black rat of Mauritius. Chromosome fusion at the tip rather than the exposed centromeres is also rare, but distinguishes Asian river buffaloes from Malaysian swamp water buffaloes.
A NEW BREED OF HUMAN?
Far far rarer than Rob heterozygotes are homozygotes with two Robs, because they can only arise from inheriting one copy of the unusual chromosome from each parent – which typically means the parents are related and inherited the Rob from a shared ancestor, like a common great-grandparent. Cases of these Rob homozygotes, who have 44 chromosomes rather than the normal 46, are exceedingly rare:
• A 1984 report describes a family with 3 adult siblings who had 44 chromosomes, #s 13 and 14 combined.
• A 1988 report tells of 3 distantly-related families in Finland, also involving #s 13 and 14, whose Rob passed in carriers through at least 9 generations, appearing in at least one homozygote.
• A 1989 paper describes a Rob between #s14 and 21 in a homozygote whose carrier parents were related.
Most oft-cited is a case report from 2013 of a 25-year-old healthy Chinese man who has 44 chromosomes because each 14 joins a 15 – a combo not seen before. His parents, both translocation carriers, were first cousins. The Chinese man’s sperm carry 21 autosomes and an X or Y, and he should be fertile – but only with a woman who is similarly chromosomally endowed. Chances are he’ll never find her. But if he does …
FROM SCIENCE TO SCI-FI
The report on the Chinese man with 44 chromosomes ends with: “The aberration can provide material for evolution. … Long term isolation of a group of individuals who are homozygous for a particular Robertsonian translocation chromosome could theoretically lead to the establishment of a new human subspecies having a full genetic complement in 44 chromosomes.”
It might have happened before. Could the 48 chromosomes of a shared ancestor of humans and chimps have branched to yield our 46 chromosomes? Fusion of chimp chromosomes 12 and 13, according to banding patterns, might have generated our larger chromosome 2.
The idea of inheriting a double dose of a Robertsonian chromosome fueling human speciation isn’t new. I wrote about it in 2002 in The Scientist, wherein Lisa Schaffer, PhD, of “Paw Print Genomics” at Washington State University, Spokane, who studied Robs, speculated, "With 1 in 1,000 individuals carrying a Robertsonian translocation, the likelihood of two carriers getting together and both transmitting their translocation is 1 in 4 million--so they are out there, just phenotypically normal."
The possibility of a new human species with 44 chromosomes lends perspective to certain science fiction plots. It may explain the origin of the bluish ghoulish subterranean Morlocks who eat the sun-loving peaceful aboveground Eloi in H.G. Wells’ future world of The Time Machine, written in 1898. Or the cannibalistic screeching humanoid monsters, our descendants, that will take over the future world depicted in last summer’s Wayward Pines.
Neither H. G. Wells or Wayward Pines’ creator Blake Crouch evoked Robertsonian translocation as a plausible route to rapid human evolution (or devolution). But sci-fi author Greg Bear came very close in his marvelous 1999 and 2003 novels Darwin's Radio and Darwin's Children.
Bear imagines that a latent retrovirus awakened in the genomes of some women pregnant in 1999 shuffled the genomes of a new generation in ways that create cells with 52 chromosomes instead of 46, thereby instantly creating a group that can successfully mate only among themselves. You’ll have to read the books to learn how and why the “virus children” are superior. Forced into camps by the fearful majority, they establish their own culture, further separating the two types of people. It is a compelling depiction of reproductive isolation leading, presumably, to speciation, with an initial chromosomal event as the impetus.
I spoke to Bear back in 2004, again for The Scientist. A self-taught scientist with a soaring imagination, Bear said, "My secrets are few. I love biology. I have been researching it in constant reading since the early 1980s. I saw very clearly that DNA must be computational, a self-organizing, self-repairing system. In the early 90s, it became clear to me that modern evolutionary theory was incomplete. I set out to find all the out-of-the-way papers that I could to prove that nature was a network, from top to bottom." The Darwin series arose from those thoughts.
I’m not very good at writing fiction and am in awe of people like Bear who can, but if I could, I’d follow up on this theme of 44-chromosome people arising and staying hidden in plain sight among those smugly having their genomes sequenced. Could social media help which, after all, wasn’t around when the Time Machine or even Darwin’s Radio were written. Alas, Facebook’s Robertsonian Translocation Support Group, founded in 2011, only has 2 posts, the first of which evokes the Lord, probably turning off those seeking scientific information.
When I’m through with my next round of textbook revisions, maybe I’ll give fiction a shot.
(This post was first published at my DNA Science blog at Public Library of Science)