Club EvMed: Of Mice and Elephants: Trade-Offs of Tumor Suppressor Duplication and Body Size Evolution in Afrotheria - Shared screen with speaker view
Charles Nunn
Thanks for joining! Please feel free to post questions, comments and perspectives in the chat… we will open for discussion after the presentation.
Cynthia Beall
Does the body size - cancer relationship pertain across populations?
James DeGregori
Larger bodies within a species can be determined by differences in signaling pathways, like for GF and IGF. So not just cell # differences.
Vinny Lynch
@Cynthia Beall, I’m only aware of studies exploring body size/cancer relationships in British and American’s
Joel Meyer
how strong is the correlation between reproductive lifespan and total lifespan across mammalian species?
Vinny Lynch
@James DeGregori the GF/IGF pathway plays a (really) important role in the developmental origins of body size differences, but ultimately the IGF pathway contributes to cell number differences — the number of osteoblasts/chondrocytes in great danes is greater than in teacup yorkies…
Neil Greenspan
Have you or others examined or considered other mechanisms for tumor control that might vary in relative effectiveness among species, such as immune-mediated elimination of malignant cells?
James DeGregori
Thanks @Vinny Lynch. The point that I was trying to make is that one cannot conclude that the increase in cell # is the reason that cancer rates are higher, as the altered signaling pathways may lead to both increased cancer risk and increased cell #s. Basically, the larger individuals may be front loading somatic investments in size as opposed to longevity and tumor suppression. Finally, is cancer incidence corrected for BMI?
Cynthia Beall
Within organisms, some organs grow in cell # for a span, and then perhaps in cell size. Others grow in number for a longer span. Might that figure into this model?
Vinny Lynch
@Neil Greenspan, we haven’t (hard to get the right samples from elephants — most importantly tumors) but others have for other organisms…
David Filice
Do you have access to other life-history characteristics such as average age of sexual maturity that could be included in your models?
Steve Schwartz (he/him/his)
I have wondered about Cynthia's question myself. In humans (and I suspect most mammals) there is substantial variation in the incidence of cancer across organ sites.
Vinny Lynch
@James DeGregori, I agree. We don’t assume that body size or lifespan are THE driver for enhanced cancer resistance, but one of the mechanisms for it…Good question about BMI. For humans the correlation is height not weight among otherwise “healthy” individuals so BMI doesn’t really come into play
David Filice
^In humans, is it fair to say that height is likely a good predictor of total number of cells, and mass is not?
Cynthia Beall
Scandinavians would be our test population then.
Vinny Lynch
@ Cynthia Beall it almost certainly does…things like Hippo signaling regulate organ size so may play are role size cells while others play a role in cell cycle exit, these mechanisms must also contribute to reduce cancer risk…in particular different rates for different tissues, organs, and even developmental origins of different tissues and cell-types
Vinny Lynch
@Cynthia Beall one could test against the height cline from northern to southern Europe
Calen Ryan
Would gene duplication be an indication of mutation rate? I’m trying to think about how you get lots of mutations/gene duplications that lead to the duplication of genes that suppress mutation/gene duplication.
Cynthia Beall
Would be an interesting study. There is debate as to the extent of genetic vs environmental contributions to the height variation. We could recruit Graham Coop.
Vinny Lynch
@Steve Schwartz, there are differences between species wrt incidence of cancer across organ sites. Humans, for example, are particularly sensitive to epithelial cancers if memory serves…I think Boddy et al (2020) explore that: https://academic.oup.com/emph/article/2020/1/187/5843791
Calen Ryan
Although maybe I’m conflating mutation rates/duplications in germline cells vs. somatic cells…
Cynthia Beall
Any is on the call.
Gunter Wagner
What part of the elephant did you do RNAseq on?
Vinny Lynch
@ Calen Ryan I think that the mutation rate in germ cells matters for evolution and somatic cells for individual cancer risk — so mutations that reduce somatic mutation rate could reduce lifetime cancer risk
Meredith Spence Beaulieu, PhD (she/her/hers)
Great discussion and questions in the chat! We’ll be opening it up for conversation soon, so feel free to raise your hand virtually at any point. (Click “Reactions” at the bottom of your screen, then “Raise Hand.”)
Cynthia Beall
Typo, sorry. Amy Boddy is on this call.
Neil Greenspan
I can imagine that allelic variation at diverse loci encoding products that intersect functionally with tumor promoting and tumor suppressing gene products might influence the incidence of malignant transformation and malignant cell survival.
Calen Ryan
@Vinny Lynch thanks. Yeah - I take it these two can vary independently? Because I’m wondering how reduction in mutation rate might also affect ‘evolvability’ if that makes any sense.
Vinny Lynch
@ Gunter Wagner not enough tissues, to be honest, we have placenta, adipose, and dermal fibroblasts…plus are working to get additional samples from ~10 different tissues...
Amy Boddy
Yes, that paper shows organ site/tissue site cancer in 36 mammals - there are species specific vulnerabilities, but data is still pretty tiny.
Vinny Lynch
@ Cynthia Beall I agree it would be a super cool study, we should recruit Graham!
Vinny Lynch
@ Neil Greenspan I agree, given that variation within populations becomes species-specific differences some of that allelic variation must interact with other genes to influencer malignant transformation and malignant cell survival…it can be like an omigenic model where there are potentially many genes that influence those things
Vinny Lynch
@ Calen Ryan if germline mutation rates influence evolvability then elephants should be less “evolvable” than things with high germline mutation rates
Aparajeya Shanker
Was there a specific type of cancer that was studied, and does this have any implication on whether the cancer is malignant or benign?
Cynthia Beall
In humans, a U-shaped curve describes the relationships between body size and survival. Stabilizing selection is the usual hypothesis.
Amy Boddy
Reports on benign and malignant cancer in elephants can be found in this paper! But we see Asian elephants get more cancer than African https://academic.oup.com/mbe/advance-article/doi/10.1093/molbev/msab127/6263836
Aparajeya Shanker
Thank you, Dr Boddy.
James DeGregori
@Cynthia Beall - Great point. Indeed, the same is true for BMI if I remember right. Too skinny is also bad.
Amy Boddy
You may predict a genetic bottleneck
Cynthia Beall
Great talk and visuals. Thank you, Manny.
Meredith Spence Beaulieu, PhD (she/her/hers)
We have time for a couple final questions!
Amy Boddy
There is likely tissue specific cancer defenses -especially for proliferative tissues
Joel Meyer
Thanks for the great talk!
Calen Ryan
Right - germline vs. somatic
James DeGregori
See recent paper from Martincorena lab showing that mutation accumulation is unlinked from cell division rates. A neuron will accumulate as many mutations as blood cells. https://www.nature.com/articles/s41586-021-03477-4
Morla Phan
Thank you so much for the talk!
James DeGregori
Awesome presentation and discussion Manny!!
Juan Vazquez
Thank you!
Amy Boddy
Great job Manny! Love the images too!!!
Calen Ryan
Thanks for the talk Manny!