PolyQ length-based molecular encoding of vocalization frequency in FOXP2

Serena Vaglietti; Veronica Villeri; Marco Dell'Oca; Chiara Marchetti; Federico Cesano; Francesca Rizzo; Dave Miller; Louis LaPierre; Ilaria Pelassa; Francisco J Monje; Luca Colnaghi; Mirella Ghirardi; Ferdinando Fiumara

doi:10.1016/j.isci.2023.108036

PolyQ length-based molecular encoding of vocalization frequency in FOXP2

iScience. 2023 Sep 27;26(10):108036. doi: 10.1016/j.isci.2023.108036. eCollection 2023 Oct 20.

Authors

Affiliations

¹ Rita Levi Montalcini Department of Neuroscience, University of Turin, 10125 Turin, Italy.
² Department of Chemistry, University of Turin, 10125 Turin, Italy.
³ Jockey Club College of Veterinary Medicine and Life Sciences, City University of Hong Kong, Kowloon Tong, Hong Kong SAR 518057, China.
⁴ Cascades Pika Watch, Oregon Zoo, Portland, OR 97221, USA.
⁵ Deptartment of Natural Science, Lower Columbia College, Longview, WA 98632, USA.
⁶ Department of Neurophysiology and Neuropharmacology, Medical University of Vienna, 1090 Vienna, Austria.
⁷ Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
⁸ School of Medicine, Vita-Salute San Raffaele University, 20132 Milan, Italy.

Abstract

The transcription factor FOXP2, a regulator of vocalization- and speech/language-related phenotypes, contains two long polyQ repeats (Q₁ and Q₂) displaying marked, still enigmatic length variation across mammals. We found that the Q₁/Q₂ length ratio quantitatively encodes vocalization frequency ranges, from the infrasonic to the ultrasonic, displaying striking convergent evolution patterns. Thus, species emitting ultrasonic vocalizations converge with bats in having a low ratio, whereas species vocalizing in the low-frequency/infrasonic range converge with elephants and whales, which have higher ratios. Similar, taxon-specific patterns were observed for the FOXP2-related protein FOXP1. At the molecular level, we observed that the FOXP2 polyQ tracts form coiled coils, assembling into condensates and fibrils, and drive liquid-liquid phase separation (LLPS). By integrating evolutionary and molecular analyses, we found that polyQ length variation related to vocalization frequency impacts FOXP2 structure, LLPS, and transcriptional activity, thus defining a novel form of polyQ length-based molecular encoding of vocalization frequency.

Keywords: Evolutionary biology; Molecular biology; Zoology.