Abnormalities associated with cervical ribs
Revised 6 Sep 26
Galis et al. (2006) in a retrospective study addressed whether selection against other than 7 cervical vertebrae in humans can be attributed to other, more harmful, abnormalities that might occur simultaneously with 7cv ribs. They used records for fetuses and infants that had died up to age 1 that had been autopsied, including full-body x-rays, in an Amsterdam hospital over an eight-year period (598 cases). The x-rays were reexamined independently by two observers for vertebral changes at the cervical/thoracic and thoracic/lumber boundaries. Cases where the fetus died before the 14th week of gestation were not used because prior to this time ossification of the vertebrae would not be sufficient to distinguish the presence of ribs. Additional cases were eliminated because of poor image quality, disagreement between the two observers, other bones obscuring the regions of interest, or poor ossification even past the 14th week. About a fourth of the cases could not be used.
In 54% of the remaining cases, ribs were observed on the 7th cervical vertebra, indicating an anterior shift in the cervical/thoracic boundary. Other vertebral anomalies were much rarer, rudimentary 1st thoracic ribs (~2%), no or rudimentary 12th thoracic rib (~3%), rib on first lumbar vertebra (~6%). For the two types of anomalies at the thoracic/lumbar boundary, they each occurred less than 1% in cases where a 7th cervical rib was observed, so there was no indication that they occurred together. The reported incidence of 7cv ribs reported for adults in other studies is always much lower, typically around 1%.
Based this decrease in incidence, the authors estimated the survival rate to birth and 1 year old when a 7th cervical rib was present. Their calculations were based on the assumptions that for the entire European population 85% of pregnancies result in live births, with an 84% survival through the first year, with negligible additional deaths until adulthood. They used an estimate of 2% of adults with a 7th cervical vertebra, which was the upper confidence limit from a collection of studies on adult skeletons.
To produce the observed prevalence of 7th cervical ribs at birth, 1 year, and adulthood, they calculated persons with 7th cervical vertebra ribs have a survival rate of 22% at birth, and 17% at 1 year, while for those without have a survival rate of 92% at birth and only slightly lower at 1 year. The initial incidence of 7th cervical vertebra ribs would be about 11%. Cervical ribs are associated with about a 9-fold increased risk of early death. There is thus strong selection against 7cv ribs.
In persons with 7cv ribs that survive beyond 1 year there is a several fold increase in some childhood cancers ( Galis 1999). However, since this is a relatively rare occurrence it likely does not have as great an selective effect as earlier deaths and likely would not greatly alter the estimate of the initial rate of 7cv ribs.
The autopsies also recorded abnormalities. The authors classified the observed abnormalities as either minor or major, likely to be fatal. In only 11% of the cases were there no observed abnormalities, and the incidence of 7cv ribs was 31%. For cases with only minor abnormalities, the incidence of 7cv ribs was 44%. For cases in which at least one major abnormality was observed (58% of cases), the incidence of 7cv rib was 61%. There thus appears to be a connection between 7cv ribs and both minor and major congenital abnormalities.
Fourteen classes of abnormalities were each observed in more than 2% of the cases, with the largest class being bleeding disorders, which may include many disparate causes. In none of the other classes was the incidence of 7cv ribs substantially different from the overall incidence. This may seem surprising giving the many times lower survival if 7cv ribs are present. This is likely case of Simpson’s paradox, which can occur when two groups of much different sizes are compaired. Although the presence of 7cv ribs is associated with an about a 9-fold increase in the probability of an early death, there are initially about 8 times as many embryos without 7cv ribs as with. Even if a particular abnormality is much more likely with 7cv ribs, none occur frequently enough to stand out.
Thus, in this study no particular abnormality that occurs solely in association with 7cv ribs occurred at a high enough rate to stand out. For the other abnormalities, their individual increases in the presence of 7cv ribs compared to no 7cv ribs were similar enough that again none stood out.
The authors attribute the association of 7cv ribs with lethality to pleiotropy effects of alleles that produce harmless changes in the position of the cervical/thoracic vertebra boundary, but may have deleterious consequences in the development of critical organs. As discussed in more detail in Background 3, Galis and Metz (2001) attributed the timing of these effects to a higher degree of interactivity between different parts of the embryo occurring around the time of the so-called phylotypic stage of development.
Since the Galis study only included fetuses that survived until the necessary ossification occurred (around week 14), it did not include miscarriages occurring earlier. A frequent estimate of 30% is given for the fraction of conceptions that end prior to birth, higher than the15% figure Galis used for week 15 fetuses. It is thus possible that the mutations associated with changes in the cervical/thoracic boundary are even more strongly selected against than this study suggests.
Why would these deleterious effects not be selected against. One possibility is that some stages of mammalian development have become so complex that mutations that might ameliorate a particular deleterious effect likely would exacerbate some other effect.
The interactions in complex systems depend on the right events occurring at the right time and location. But rates of the interacting processes are affected by the localized temperature. In ectotherms, this is coordinated by critical processes having similar temperature dependence (Background 9)g.
The increasing homeothermic evolution in the mammalian lineage allowed for processes to be optimized over a narrower temperature range. Exploration 2 examines the possibility that this allowed ever more complex developmental processes. If this actually the case, this would be the driving force for ever stricter limitation on temperature variability, especially during the period of highest interactivity. I have called this the Goldilocks Hypothesis, and Exploration 1 is a survey of variation of temperature variability throughout gestation in mammals to examine this hypothesis.
A better understanding of why 7cv ribs are associated with abnormalities is likely to occur only if some of these pleiotropic alleles can be identified. Presumably for ethical or privacy issues, studies such as Galis et al. (2006) have not reported much information on the medical circumstances which led to autopsies being performed. It is thus difficult to determine how representative this study was of deaths in the general population. It was stated that the study included fetuses from abortions for medical reasons. In Exploration 3 I will discuss some possibilities for the genes from which these pleiotropic effects might arise.